Low-molecular serine proteases inhibitors comprising polyhydroxy-alkyl and polyhydroxy-cycloalkyl radicals

ABSTRACT

The invention relates to novel amidines and quanidines, the production and use thereof and the use thereof as trypsine-type serine protease competitive inhibitors, especially thrombine and compliment proteases CIs and C1r. The invention also relates to pharmaceutical compositions which contain said compounds as active ingredients, in addition to the use of the compounds as thrombine inhibitors, anticoagulants, compliment inhibitors and anti-inflammatory agents. The novel compositions are characterised by the linkage of a serine protease inhibitor having amidine or quanidine functions with an alkyl radical having two or more hydroxyl functions, whereby said alkyl radical is derived from sugar derivates.Several sugar structural components or components derived from sugar can therefore be linked to each other. Said principle of linking sugar derivates enables oral active compounds to be obtained.

DESCRIPTION

[0001] The present invention relates to novel amidines and guanidines,to the production thereof, and to the use thereof as competitiveinhibitors of trypsin-like serine proteases, particularly thrombin andthe complement proteases C1s and C1r.

[0002] The invention also relates to pharmaceutical compositionscontaining said compounds as active ingredients, and also to the use ofsaid compounds as thrombin inhibitors, anticoagulants, complementinhibitors, or anti-inflammatory agents. A characteristic of the novelcompounds is their ability to link a serin protease inhibitor having anamidine or guanidine function to an alkyl group having two or morehydroxyl functions and derived from sugar derivatives. Thus a number ofsugar building blocks or building blocks derived from sugars can belinked. This principle of coupling with sugar derivatives providesorally active compounds.

[0003] Preferred sugar derivatives include all types of reductive sugarswhich reductively react with a terminal amine function of the inhibitor.

[0004] Reductive sugars are sugars which are capable of reducing Cu(II)ions in solution to Cu(I) oxide.

[0005] Reductive sugars include:

[0006] Any of the aldoses (whether in open-chain or cyclic form) (eg,trioses; or tetraoses such as erythrose and threose; or pentoses such asarabinose, xylose, rhamnose, fucose, and ribose; or hexoses such asglucose, mannose, galactose, and 2-deoxy-D-glucose, etc.);

[0007] any of the (hydroxy)ketoses. Hydroxyketoses contain a HOCH₂—COgroup. Fructose and ribulose are examples thereof.

[0008] Di-, oligo- and poly-saccharides containing a hemiacetal, such aslactose, melibiose, maltose, maltotriose, maltotetraose, maltohexaose,or cellulose oligomers such as cellobiose, cellotriose or dextranoligomers or pullulan oligomers or inulin oligomers, etc.

[0009] Sugar derivatives and complex oligosaccharides containing ahemiacetal, such as glucuronic acid, galacturonic acid,2-deoxy-D-glucose, 2-deoxy-2-fluoro-D-glucose, glucosamine,N-acetyl-D-glucosamine, oligomers of pectin and hyaluronic acid.

[0010] Examples of other preferred sugar derivatives are sugar acidswhich react with a terminal amine function of the inhibitor via the acylfunction.

[0011] Thrombin is a member of the group of serine proteases and plays acentral role as terminal enzyme in the blood coagulation cascade. Boththe intrinsic and the extrinsic coagulation cascades cause, via a numberof intensification stages, the production of thrombin from prothrombin.Thrombin-catalyzed cleavage of fibrinogen to fibrin then triggers bloodcoagulation and aggregation of the thrombocytes, which in turn increasethe formation of thrombin by binding platelet factor 3 and coagulationfactor XIII as well as via a whole series of highly active mediators.

[0012] The formation and action of thrombin are central events in thegenesis of both white arterial thrombi and red venous thrombi and aretherefore potentially effective points of attack for pharmacologicalagents. Thrombin inhibitors are, unlike heparin, capably of completelyinhibiting, simultaneously, the action of free thrombin and thrombinbound to thrombocytes, irrespective of co-factors. They can prevent, inthe acute phase, thrombo-embolic events following percutane transluminalcoronary angioplasty (PTCA) and cell lysis and serve as anticoagulantsin extracorporeal recirculation (heartlung apparatus, haemodialysis).They can also serve in a general way for the prophylaxis of thrombosis,for example, after surgical operations.

[0013] Inhibitors of thrombin are suitable for the therapy andprophylaxis of

[0014] diseases whose pathogenetic mechanism is based, directly orindirectly, on the proteolytic action of thrombin,

[0015] diseases whose pathogenetic mechanism is based on thethrombin-dependent activation of receptors and signal transductions,

[0016] diseases accompanying the stimulation or inhibition of geneexpressions in somatic cells,

[0017] diseases due to the mitogenetic action of thrombin,

[0018] diseases caused by a thrombin-dependent change in contractilityand permeability of epithel cells,

[0019] thrombin-dependent thrombo-embolic events,

[0020] disseminated intravascular coagulation (DIC),

[0021] re-occlusion, and for shortening the reperfusion time in cases ofco-medication with thrombolytics,

[0022] early re-occlusion and later restenosization followingPTCA,—thrombin-induced proliferation of smooth muscle cells,—theaccumulation of active thrombin in the CNS,

[0023] tumor growth, and to counteract adhesion and carcinosis of tumorcells.

[0024] A number of thrombin inhibitors of the D-Phe-Pro-Arg type isknown for which good thrombin inhibition in vitro has been described: WO9702284-A, WO 9429336-A1, WO 9857932-A1, WO 9929664-A1, U.S. Pat. No.5,939,392-A, WO 200035869-A1, WO 200042059-A1, DE 4421052-A1, DE4443390-A1, DE 19506610-A1, WO 9625426-A1, DE 19504504-A1, DE19632772-A1, DE 19632773-A1, WO 9937611-A1, WO 9937668-A1, WO9523609-A1, U.S. Pat. No. 5,705,487-1, WO 9749404-A1, EP-669317-A1, WO9705108-A1, EP 0672658. However, some of this compounds exhibit low oralactivity.

[0025] In WO 9965934 and Bioorg. Med. Chem. Lett., 9(14), 2013-2018,1999, benzamidine derivatives of the NAPAP type are described which arecoupled through a long spacer to pentasaccharides and thus show a dualantithrombotic principle of action. However, no oral activity of thesecompounds is described.

[0026] Activation of the complement system ultimately leads, through acascade of ca 30 proteins, inter alia, to lysis of cells.Simultaneously, molecules are liberated which, like C5a, can lead to aninflammatory reaction. Under physiological conditions, the complementsystem provides a defence mechanism against foreign bodies, such asviruses, fungi, bacteria, or cancer cells. Activation by various routestakes place initially via proteases. By activation, these proteases aremade capable of activating other molecules of the complement system,which may in turn be inactive proteases. Under physiological conditions,this system, like blood coagulation, is under the control of regulatoryproteins, which counteract exuberant activation of the complementsystem. In such cases it is not advantageous to take measures to inhibitthe complement system.

[0027] In some cases the complement system overreacts, however, and thuscontributes to the pathologic physiology of diseases. In such cases,therapeutic action on the complement system causing inhibition ormodulation of the exuberant reaction is desirable. Inhibition of thecomplement system is possible at various levels in the complement systemby inhibition of various effectors. The literature provides examples ofthe inhibition of serine proteases at the C1 level with the aid of theC1 esterase inhibitor as well as inhibition at the level of C3 or C5convertases by means of soluble complement receptor CR1 (sCR1),inhibition at the level of C5 by means of antibodies, and inhibition atthe level of C5a by means of antibodies or antagonists. The tools usedfor achieving inhibition in the above examples are proteins. In thepresent invention, low-molecular substances are described which are usedfor inhibition of the complement system.

[0028] For such inhibition of the complement system some proteasesutilizing various activation routes are particularly suitable. Of theclass of thrombin-like serine proteases, such proteases are thecomplement proteases C1r and C1s for the classical route, factor D andfactor B for the alternative route, and also MASP I and MASP II for theMBL route. The inhibition of these proteases then leads to are-establishment of the physiological control of the complement systemin the above diseases or pathophysiological states.

[0029] Generally speaking, all inflammatory disorders accompanied by theimmigration of neutrophilic blood cells must be expected to involveactivation of the complement system. Thus it is expected that with allof these disorders an improvement in the pathophysiological state willbe achieved by causing inhibition of parts of the complement system.

[0030] The activation of complement is associated with the followingdiseases or pathophysiological states:

[0031] reperfusion syndrome following ischaemia; ischemic states occurduring, say, operations involving the use of heartlung apparatus;operations in which blood vessels are generally compressed to avoidsevere haemorrhage; myocardial infarction; thrombo-embolic cerebralinfarct; pulmonary thrombosis, etc.;

[0032] hyper-acute rejection of an organ; specifically in the case ofxenotransplantations;

[0033] failure of an organ, for example multiple failure of an organ orARDS (adult respiratory distress syndrome);

[0034] diseases caused by injuries (skull injuries) or multipleinjuries, such as thermal injuries (burns), and anaphylactic shock;

[0035] sepsis; “vascular leak syndrom”: with sepsis and followingtreatment with biological agents, such as interleukin 2, or followingtransplantation;

[0036] Alzheimer's disease and also other inflammatory neurologicaldiseases such as Myastenia graevis, multiple sclerosis, cerebral lupus,Guillain Barré syndrome; forms of meningitis; forms of encaphilitis;

[0037] systemic Lupus erythematosus (SLE);

[0038] rheumatoid arthritis and other inflammatory diseases in therheumatoid disease cycle, such as Behcet's syndrome; juvenile rheumatoidarthritis;

[0039] renal inflammation of various geneses, such as glomerularnephritis, or Lupus nephriti;

[0040] pancreatitis;

[0041] asthma; chronic bronchitis;

[0042] complications arising in dialysis for renal insufficiency;vasculitis; thyroiditis;

[0043] ulcerative colitis and also other inflammable disorders of thegastro-intestinal tract;

[0044] auto-immune disorders.

[0045] inhibition of the complement system; for example, the use of theC1s inhibitors of the invention can alleviate the side effects ofpharmaceutical preparations based on activation of the complement systemand reduce resultant hypersensitivity reactions.

[0046] Accordingly, treatment of the above mentioned diseases orpathophysiological states with complement inhibitors is desirable,particularly treatment with low-molecular inhibitors.

[0047] PUT and FUT derivatives are amidinophenol esters andamidinonaphthol esters respectively and have been described ascomplement inhibitors (eg, Immunology (1983), 49(4), 685-91).

[0048] Inhibitors are desired which inhibit C1s and/or C1r, but notfactor D. Preferably, there should be no inhibition of lysis enzymessuch as t-PA and plasmin.

[0049] Special preference is given to substances which effectivelyinhibit thrombin or C1s and C1r.

PHARMACOLOGICAL EXAMPLES Example A

[0050] Thrombin Time

[0051] Reagents: thrombin reagent (List No. 126,594, Boehringer,Mannheim, Germany)

[0052] Preparation of citrate plasm:

[0053] 9 parts of venous human blood from the V. cephalica are mixedwith 1 part of sodium citrate solution (0.11 mol/L), followed bycentrifugation. The plasma can be stored at −20° C.

[0054] Experimental method:

[0055] 50 μl of the solution of the test probe and 50 μl of citrateplasma are incubated for 2 minutes at 37° C. (CL8, ball type, Bender &Hobein, Munich, FRG). Then 100 μl of thrombin reagent (37° C.) areadded. The time taken for the fibrin clot to form is determined. TheEC₁₀₀ values give the concentration at which the thrombin time isdoubled.

Example B

[0056] Chromogenic Test for Thrombin Inhibitors

[0057] Reagents: human plasma thrombin (No. T 8885, Sigma, Deisenhofen,Germany)

[0058] substrate: H-D-Phe-Pip-Arg-pNA2HCl (S-2238, Chromogenix,Mölndahl, Sweden)

[0059] buffer: Tris 50 mmol/L, NaCl 154 mmol/L, pH 8.0

[0060] Experimental procedure:

[0061] The chromogenic test can be carried out in microtitration plates.10 μl of the solution of substance in dimethyl sulfoxide are added to250 μl of buffer containing thrombin (final concentration 0.1 NIHunits/mL) and incubated over a period of 5 minutes at from 20° to 28° C.The test is initiated by the addition of 50 μL of substrate solution inbuffer (final concentration 100 μmmol/L), the mixture being incubated at28° C., and, following a period of 5 minutes, the test is stopped by theaddition of 50 μL of citric acid (35%). The absorption is measured at405/630 nm.

Example C

[0062] Platelet Aggregation in the Platelet-Enriched Plasma

[0063] Reagents: human plasma thrombin (No. T-8885, Sigma, Deisenhofen,Germany)

[0064] Production of the citrate-enriched platelet-enriched plasm:

[0065] Venous blood from the Vena cephalica of healthy drug-free testpersons is collected. The blood is mixed 9:1 with 0.13M trisodiumcitrate.

[0066] Platelet-enriched plasma (PRP) is produced by centrifugation at250×g (for 10 minutes at room temperature). Platelet-impoverished plasma(PPP) is produced by centrifugation for 20 minutes at 3600×g. PRP andPPP can be kept in sealed PE vessels for a period of 3 hours at roomtemperature. The platelet concentration is measured with a cytometer andshould be from 2.5 to 2.8·10⁻⁸/mL.

[0067] Experimental method:

[0068] The platelet aggregation is measured by turbitrimetric titrationat 37° C. (PAP 4, Biodata Corporation, Horsham, Pa., USA). Beforethrombin is added, 215.6 μL of PRP are incubated for 3 minutes with 2.2μL of test probe and then stirred over a period of 2 minutes at 1000rpm. At a final concentration of 0.15 NIH units/mL, 2.2 μL of thrombinsolution produce the maximum aggregation effect at 37° C./1000 rpm. Theinhibited effect of the test probes is determined by comparing the rate(rise) of aggregation of thrombin without test substance with the rateof aggregation of thrombin with test substance at variousconcentrations.

Example D

[0069] Color Substrate Test for C1r Inhibition

[0070] Reagents: C1r from human plasma, activated, two-chain(dual-chain)form (purity: ca 95% according to SDS gel). No foreign protease activitycould be detected.

[0071] substrate: Cbz-Gly-Arg-S-Bzl, Product No. WBAS012, (Polypeptide,D38304 Wolfenbüttel, Germany).

[0072] color reagent: DTNB (5.5′-dinitro-bis(2-nitrobenzoic acid)) (No.43,760, Fluka, CH 9470 Buchs, Switzerland). buffer: 150 mM Tris/HCl, pH7.50

[0073] Test procudure:

[0074] The color substrate test for determining the C1s activity iscarried out in 96-well microtitration plates.

[0075] 10 μL of inhibitor solution in 20% strength dimethyl sulfoxide(dimethyl sulfoxide diluted with 15 mM Tris/HCl, pH 7.50) are added to140 μL of test buffer containing C1s in a final concentration of 0.013U/mL and DTNB in a final concentration of 0.27 mM/L. Incubation wascarried out over a period of 10 minutes at from 20° to 25° C.

[0076] The test is started by the addition of 50 μL of a 1.5 mMsubstrate solution in 30% strength dimethyl sulfoxide (finalconcentration 0.375 mM/L). Following an incubation period of 30 minutesat from 20° to 25° C., the absorbance of each well at 405 nm is measuredin a double-beam microtitrimetric plate photometer against a blankreading (without enzyme).

[0077] Measuring criterion:

[0078] IC₅₀: inhibitor concentration required in order to reduce theamidolytic C1r activity to 50%.

[0079] Statistical results:

[0080] Calculation is based on the absorbance as a function of inhibitorconcentration.

Example E

[0081] Material and Methods: Color Substrate Test for C1s Inhibition

[0082] Reagents: C1s from human plasm, activated, two-chain(dual-chain)form (purity: ca 95% according to SDS gel). No foreign protease activitycould be detected.

[0083] Substrate: Cbz-Gly-Arg-S-Bzl, Product No. WBAS012, (PolyPeptide,D38304 Wolfenbüttel, Germany)

[0084] Color reagent: DTNB (5.5′-dinitro-bis(2-nitrobenzoic acid)) (No.43,760, Fluka, CH 9470 Buchs, Switzerland) buffer: 150 mM Tris/HCl, pH7.50

[0085] Test procedure:

[0086] The color substrate test for determining the C1s activity iscarried out in 96-well microtitration plates.

[0087] 10 μL of the inhibitor solution in 20% strength dimethylsulfoxide (dimethyl sulfoxide diluted with 15 mM Tris/HCl, pH 7.50) areadded to 140 μL of test buffer containing C1s in a final concentrationof 0.013 U/mL and DTNB in a final concentration of 0.27 mM/L. Incubationis carried out over a period of 10 minutes at from 20° to 25° C. Thetest is started by the addition of 50 μL of a 1.5 mM substrate solutionin 30% strength dimethyl sulfoxide (final concentration 0.375 mmol/L).Following an incubation period of 30 minutes at from 20° to 25° C., theabsorbance of each well at 405 nm is measured in a double-beammicrotitrimetric plate photometer against a blank reading (withoutenzyme).

[0088] Measuring criterion:

[0089] IC₅₀: inhibitor concentration required in order to reduce theamidolytic C1s activity to 50%.

[0090] Statistical results:

[0091] Calculation is based on the absorbance as a function of inhibitorconcentration.

Example F

[0092] Confirmation of the Inhibition of Complement by the ClassicalRoute Employing a Hemolytic Test

[0093] For measuring potential complement inhibitors use is made, in themanner of diagnostic tests, of a test for measuring the classical route(literature: Complement, A practical Approach; Oxford University Press;1997; pp 20 et seq). The source of complement used for this purpose ishuman serum. A test of similar layout is, however, also carried out onvarious serums of other species in a similar manner. The indicatingsystem used comprises erythrocytes of sheep. The antibody-dependentlysis of these cells and the thus exuded haemoglobin are a measure ofthe complement activity. Reagents, biochemical products: Veronal Merck#2760500 Na-Veronal Merck #500538 NaCl Merck #1.06404 MgCl₂ × 6H₂O Baker#0162 CaCl₂ × 6H₂O Riedel de Haen #31307 Gelatin Merck #1.04078.0500EDTA Roth #8043.2 Alsevers soln. Gibco #15190-044 Penicillin Gruenenthal#P1507 10 mega Ambozeptor Behring #ORLC Stock solutions: VBS stocksolution: 2.875 g/L Veronal; 1.875 g/L Na-Veronal; 42.5 g/L NaCl Ca/Mgstock solution: 0.15 M Ca++, 1 M Mg++ EDTA stock solution:  0.1 M, pH7.5 Buffer: GVBS buffer: VBS stock solution diluted 1:5 with Finn Aqua;1 g/L of gelatin dissolved in some buffer at elevated temperature GVBS++buffer: Ca/Mg stock solution diluted 1:1000 in GVBS buffer GVBS/EDTAbuffer: EDTA stock solution diluted 1:10 in GVBS buffer

[0094] Biogenic components:

[0095] Sheep erythrocytes (SRBC): the blood of a wether was mixed 1:1(v/v) with Alsevers solution and filtered through glass wool. There wasadded {fraction (1/10)} volume of EDTA stock solution and 1 spatula tipof penicillin. Human serum: after centrifuiging off the clotted portionsat 4° C., the supernatant liquor was stored in aliquot portions at −70°C. All of the measurements were carried out on one batch. No essentialdeviations from serum of other test objects were found.

[0096] Procedure:

[0097] 1. Sensitization of the erythrocytes:

[0098] SRBC's were washed three times with GVBS buffer. The number ofcells was then adjusted to 5.00E+08 cells/mL in GVBS/EDTA buffer.Ambozeptor was added in a dilution of 1:600 and the SRBC's were thensensitized with antibody by incubation for 30 min at 37° C. withagitation. The cells were then washed three times with GVBS buffer at 4°C., then absorbed in GVBS++ buffer and adjusted to a cell count of5×10⁸.

[0099] 2. Lysis batch:

[0100] Inhibitors were pre-incubated in GVBS++ for 10 min at 37° C. in avolume of 100 μL in various concentrations with human serum or serum ofother species in suitable dilutions (for example 1:80 for human serum asuitable dilution is one at which ca 80% of the maximum cell lysisattainable with serum is achieved). 50 μL of sensitized SRBC's in GVBS++were then added. Following incubation for one hour at 37° C. withagitation, the SRBC's were removed by centrifugation (5 minutes, 2500rpm, 4° C.). 130 μL of the cell-free supernatant were transferred to a96-well plate. The results were gained by measuring at 540 nm againstGVBS++ buffer.

[0101] Evaluation was based on the absorption values at 540 nm.

[0102] (1): background; cells without serum

[0103] (3): 100% cell lysis; cells with serum

[0104] (x): readings on test probes

[0105] Calculation:${\% \quad {cell}\quad {lysis}} = \frac{(x) - {(1) \times 100\%}}{(3) - (1)}$

Example G

[0106] Inhibitors Tested for Inhibition of Protease Factor D

[0107] Factor D plays a central role in the alternative route of thecomplement system. By reason of the low plasma concentration of factorD, the enzymatic step of cleavage of factor B by factor D represents therate-limiting step in the alternative way of achieving complementactivation. On account of the limiting role played by this enzyme in thealternative route, factor D is a target for the inhibition of thecomplement system.

[0108] The commercial substrate Z-Lys-S-Bzl * HCl is converted by theenzyme factor D (literature: C. M. Kam et al, J. Biol. Chem. 2623444-3451, 1987). Detection of the cleaved substrate is effected byreaction with Ellmann's reagent. The resulting product is detectedspectrophotometrically. The reaction can be monitored on-line. Thismakes it possible to take enzyme-kinetic readings.

[0109] Material: Chemicals: Factor D Calbiochem 341273 Ellmann's ReagentSigma D 8130 Z-Lys-S-Bzl * HCl (= substrate) Bachem M 1300 50 mg/mL(MeOH) NaCl Riedel De Haen 13423 Triton-X-100 Aldrich 23,472-9Tris(hydroxymethyl)aminomethane Merck Dimethylformamide (DMF) Buffer: 50 mM Tris 150 mM NaCl 0.01% triton-X-100 pH 7.6 Stock solutions:Substrate 20 mM (8.46 mg/mL = 16.92 μL (50 mg/mL) + 83.1 μL H₂O)Ellmann's Reagent 10 mM (3.963 mg/mL) in DMF Factor D 0.1 mg/mL Samples(inhibitors) 10⁻²M DMSO Procedure: Batches: Blank reading: 140 μL ofbuffer + 4.5 μL of substrate (0.6 mM) + 4.5 μL of Ellmann's reagent (0.3mM) Positive control: 140 μL of buffer + 4.5 μL of substrate (0.6 mM) +4.5 μL of Ellmann's reagent (0.3 mM) + 5 μL of factor D Sample readings:140 μL of buffer + 4.5 μL of substrate (0.6 mM) + 4.5 μL of Ellmann'sreagent (0.3 mM) + 1.5 μL of sample (10⁻⁴ M) + 5 μL of factor D

[0110] The batches are pipetted together into microtitration plates.After mixing the buffer, substrate and Ellmann's reagent (inhibitor whenrequired), the enzyme reaction is initiated by the addition of 5 μL offactor D in each case. Incubation takes place at room temperature for 60min.

[0111] Readings:

[0112] Readings are taken at 405 nm over a period of 1 hour at intervalsof 3 minutes.

[0113] Evaluation:

[0114] The results are plotted as a graph. The change in absorption perminute (Delta OD per minute; rising) is relevant for the comparison ofinhibitors, since K_(i) value of inhibitors can be ascertainedtherefrom.

[0115] In this test, the serin protease inhibitor FUT-175; Futhan,Torii; Japan was co-used as effective inhibitor.

Example H

[0116] Confirmation of the inhibition of complement by the alternativeroute was obtained using a hemolytic test (literature: Complement, Apractical Approach; Oxford University Press; 1997, pp 20 et seq).

[0117] The test is carried out on the lines of clinical tests. The testcan be modified by additional activation by means of, say, Zymosan orcobra venom factor. Material: EGTA (ethylene-bis(oxyethylenenitrilo)Boehringer 1093053 tetracetic acid Mannheim MgCl₂.6 H₂O Merck 5833,0250NaCl Merck 1.06404.1000 D-glucose Cerestar Veronal Merck 2760500Na-Veronal Merck 500538 VBS - stock solution (5x) gelatin Veronal bufferPD Dr. Kirschfink; University of Heidelberg, Institute for Immunology;Gelatin Merck 1.04078.0500 Tris(hydroxymethyl)aminomethane Merck1.08382.0100 CaCl₂ Merck No. 2382

[0118] Human serum was either procured from various contractors (eg,Sigma) or obtained from test persons in the polyclinic department ofBASF Süd.

[0119] Guinea pig's blood was extracted and diluted 2:8 in citratesolution. Several batches were used without apparent differences. Stocksolutions: VBS stock solution: 2.875 g/L Veronal 1.875 g/L Na-Veronal 42.5 g/L NaCl GVBS: VBS stock solution diluted 1:5 with water (FinnAqua) 0.1% gelatin added and heated until gelatin had dissolved and thencooled 100 mM EGTA: 38.04 mg EGTA diluted in 500 mL of Finn Aqua andslowly treated with 10 M NaOH to raise the pH to 7.5 until dissolved,then made up to 1 L. Saline: 0.9% NaCl in water (Finn Aqua) GTB: 0.15 mMCaCl₂  141 mM NaCl  0.5 mM MgCl₂.6 H₂O   10 mM Tris 0.1% gelatin pH7.2-7.3

[0120] Procedure:

[0121] 1. Cell preparation:

[0122] The erythrocytes in the guinea pig's blood were washed with GTB anumber of times by centrifugation (5 minutes at 1000 rpm) until thesupernatant liquor was clear. The cell count was adjusted to 2·10⁹cells/mL.

[0123] 2. Procedure: the individual batches were incubated withagitation over a period of 30 minutes at 37° C. The assay was thenstopped with 480 μL of ice-cold saline (physical solution of commonsalt) and the cells were removed by centrifugation at 5000 rpm over aperiod of 5 minutes. 200 μL of the supernatant liquor were measured at405 nm by transfer thereof to a microtitration plate and evaluation in amicrotitration plate photometer. Pipetting table (quantities in μL)Background + Background 100% Lysis + factor D (− Max. lysis (−serum) 100% Lysis factor D serum (water) Cells 20 20 20 20 20 Serum 20 20 Mg-EGTA480 480 480 480 Factor D 0.5 μg 0.5 μg Saline (to stop 480 480 480 480the test H₂O 980

[0124] Calculation:${\% \quad {cell}\quad {lysis}} = \frac{(x) - {(1) \times 100\%}}{(3) - (1)}$

Example I

[0125] Pharmacokinetics and Clotting Parameters in Rats

[0126] The test probes are dissolved in isotonic salt solution justprior to administration to Sprague Dawley rats in an awake state. Theadministration doses are 1 ml/kg for intravenous Bolus injection intothe cercal vein and 10 ml/kg for oral administration, which is carriedout per pharyngeal tube. Withdrawals of blood are made, if not otherwisestated, one hour after oral administration of 21.5 mg·kg⁻¹ orintravenous administration of 1.0 mg·kg⁻¹ of the test probe orcorresponding vehicle (for control). Five minutes before the withdrawalof blood, the animals are narcotized by i.p. administration of 25%strength urethane solution (dosage 1 g·kg⁻¹ i.p.) in physiologicalsaline. The A. carotis is prepared and catheterized, and blood samples(2 mL) are taken in citrate tubules (1.5 parts of citrate plus 8.5 partsof blood). Directly after blood sampling, the ecarin clotting time (ECT)in whole blood is determined. Following preparation of the plasma bycentrifugation, the plasma thrombin time and the activated partialthromboplastin time (APTT) are determined with the aid of acoagulometer.

[0127] Clotting parameters:

[0128] Ecarin clotting time (ECT): 100 μL of citrate blood are incubatedfor 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender & Hobein,Munich, German Federal Republic). Following the addition of 100 μL ofwarmed (37° C.) ecarin reagent (Pentapharm), the time taken for a fibrinclot to form is determined.

[0129] Activated thromboplastin time (APTT): 50 μL of citrate plasma and50 μL of PTT reagent (Pathrombin, Behring) are mixed and incubated for 2min at 37° C. in a coagulometer (CL 8, ball type, Bender & Hobein,Munich, German Federal Republic). Following the addition of 50 μL ofwarmed (37° C.) calcium chloride, the time taken for a fibrin clot toform is determined.

[0130] Thrombin time (TT): 100 μL of citrate-treated plasma areincubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender& Hobein, Munich, German Federal Republic). Following the addition of100 μL of warmed (37° C.) thrombin reagent (Boehringer Mannheim), thetime taken for a fibrin clot to form is determined.

Example J

[0131] Pharmacokinetics and Clotting Parameters in Dogs

[0132] The test probes are dissolved in isotonic salt solution justprior to administration to half-breed dogs. The administration doses are0.1 ml/kg for intravenous Bolus injection and 1 ml/kg for oraladministration, which is carried out per pharyngeal tube. Samples ofvenous blood (2 mL) are taken in citrate tubules prior to and also 5,10, 20, 30, 45, 60, 90, 120, 180, 240, 300, and 360 min (if required,420 min, 480 min, and 24 H) after intravenous administration of 1.0mg/kg or prior to and also 10, 20, 30, 60, 120, 180, 240, 300, 360, 480min and 24 h after oral dosage of 4.64 mg/kg. Directly after bloodsampling, the ecarin clotting time (ECT) in whole blood is determined.Following preparation of the plasma by centrifugation, the plasmathrombin time and the activated partial thromboplastin time (APTT) aredetermine with the aid of a coagulometer.

[0133] In addition, the anti-F-IIa activity (ATU/mL) and theconcentration of the substance are determined by their anti-F-IIaactivity in the plasma by means of chromogenic (S 2238) thrombin assay,calibration curves with r-hirudin and the test substance being used.

[0134] The plasma concentration of the test probe forms the basis ofcalculation of the pharmacokinetic parameters: time to maximum plasmaconcentration (T max), maximum plasma concentration; plasma half-life,t_(0.5); area under curve (AUC); and resorbed portion of the test probe(F).

[0135] Clotting parameters:

[0136] Ecarin clotting time (ECr): 100 μL citrate-treated blood areincubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender& Hobein, Munich, German Federal Republic). Following the addition of100 μL of warmed (37° C.) ecarin reagent (Pentapharm), the time takenfor a fibrin clot to form is determined.

[0137] Activated thromboplastin time (APTT): 50 μL citrate-treatedplasma and 50 μL of PTT reagent (Pathrombin, Behring) are mixed andincubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender& Hobein, Munich, German Federal Republic). Following the addition of 50μL of warmed (37° C.) calcium chloride, the time taken for a fibrin clotto form is determined.

[0138] Thrombin time (TT): 100 μL of citrate-treated plasma is incubatedfor 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender & Hobein,Munich, German Federal Republic). Following the addition of 100 μL ofwarmed (37° C.) thrombin reagent (Boehringer Mannheim), the time takenfor a fibrin clot to form is determined.

[0139] The present invention relates to peptide substances andpeptidomimetic substances, to the preparation thereof, and to the usethereof as thrombin inhibitors or complement inhibitors. In particular,the substances concerned are those having an amidine group as terminalgroup on the one hand and a polyhydroxyalkyl or polyhydroxcycloalkylgroup—which can comprise several units as the second terminal group onthe other hand.

[0140] The invention relates to the use of these novel substances forthe production of thrombin inhibitors, complement inhibitors, and,specifically, inhibitors of C1s and C1r.

[0141] In particular, the invention relates to the use of chemicallystable substances of the general formula I, to their tautomers andpharmacologically compatible salts and prodrugs for the production ofmedicinal drugs for the treatment and prophylaxis of diseases which canbe alleviated or cured by partial or complete inhibition, particularlyselective inhibition, of thrombin or C1s and/or C1r.

[0142] Formula I has the general structure

A—B—D—E—G—K—L  (I),

[0143] in which

[0144] A stands for H, CH₃, H—(R^(A1))i^(A) in which

[0145] R^(A1) denotes

[0146]  in which R^(A2) denotes H, NH₂, NH—COCH₃, F, or NHCHO,

[0147] R^(A3) denotes H or CH₂OH,

[0148] R^(A4) denotes H, CH₃, or COOH,

[0149]_(i)A is 1 to 20,

[0150]_(j)A is 0, 1, or 2,

[0151]_(k)A is 2 or 3,

[0152]_(l)A is 0 or 1,

[0153]_(m)A is 0, 1, or 2,

[0154]_(n)A is 0, 1, or 2,

[0155] the groups R^(A1) being the same or different when _(i)A isgreater than 1;

[0156] B denotes

[0157] A—B can stand for

[0158]  or for a neuraminic acid radical or N-acetylneuraminic acidradical bonded through the carboxyl function,

[0159]  in which

[0160] R^(B1) denotes H, CH₂OH, or C₁₋₄ alkyl,

[0161] R^(B2) denotes H, NH₂, NH—COCH₃, F, or NHCHO,

[0162] R^(B3) denotes H, C₁₋₄ alkyl, CH₂—O—(C₁₋₄ alkyl), COOH, F,NH—COCH₃, or CONH₂,

[0163] R^(B4) denotes H, C₁₋₄ alkyl, CH₂—O—(C₁₋₄ alkyl), COOH, or CHO,in which latter case intramolecular acetal formation may take place,

[0164] R^(B5) denotes H, C₁₋₄ alkyl, CH₂—O—(C₁₋₄ alkyl), or COOH,

[0165]_(k)B is 0 or 1,

[0166]_(l)B is 0, 1, 2, or 3 (_(l)B≠0 when A=R^(B1)=R^(B3)=H,_(m)B=_(k)B=0 and D is a bond),

[0167]_(m)B is 0, 1, 2, 3, or 4,

[0168]_(n)B is 0, 1, 2, or 3,

[0169] R^(B6) denotes C₁₋₄ alkyl, phenyl, or benzyl, and

[0170] R^(B7) denotes H, C₁₋₄ alkyl, phenyl, or benzyl;

[0171] D stands for a bond or for

[0172]  in which

[0173] R^(D1) denotes H or C₁₋₄ alkyl,

[0174] R^(D2) denotes a bond or C₁₋₄ alkyl,

[0175] R^(D3) denotes

[0176]  in which _(l)D is 1, 2, 3, 4, 5, or 6,

[0177] R^(D5) denotes H, C₁₋₄ alkyl, or Cl, and

[0178] R^(D6) denotes H or CH₃,

[0179] and in which a further aromatic or aliphatic ring can becondensed onto the ring systems defined for R^(D3), and

[0180] R^(D4) denotes a bond, C₁₋₄ alkyl, CO, SO₂, or CH₂—CO;

[0181] E stands for

[0182]  in which

[0183]_(k)E is 0, 1, or 2,

[0184]_(l)E is 0, 1, or 2,

[0185]_(m)E is 0, 1, 2, or 3,

[0186]_(n)E is 0, 1, or 2,

[0187]_(p)E is 0, 1, or 2,

[0188] R^(E1) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl (particularlyphenyl or naphthyl), heteroaryl (particularly pyridyl, thienyl,imidazolyl, or indolyl), and C₃₋₈ cycloalkyl having a phenyl ringcondensed thereto, which groups may carry up to three identical ordifferent substituents selected from the group consisting of C₁₋₆ alkyl,OH, O—(C₁₋₆ alkyl), F, Cl, and Br,

[0189] R^(E1) may also denote R^(E4)OCO—CH₂— (where R^(E4) denotes H,C₁₋₁₂ alkyl, or C₁₋₃ alkylaryl),

[0190] R^(E2) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl (particularlyphenyl or naphthyl), heteroaryl (particularly pyridyl, furyl, thienyl,imidazolyl, or indolyl), tetrahydropyranyl, tetrahydrothiopyranyl,diphenylmethyl, and dicyclohexylmethyl, C₃₋₈ cycloalkyl having a phenylring condensed thereto, which groups may carry up to three identical ordifferent substituents selected from the group consisting of C₁₋₆ alkyl,OH, O—(C₁₋₆ alkyl), F, Cl, and Br, and may also denote CH(CH₃)OH orCH(CF₃)₂,

[0191] R^(E3) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl(particularlyphenylornaphthyl), heteroaryl (particularly pyridyl,theinyl, imidazolyl, or indolyl), and C₃₋₈ cycloalkyl having a phenylring condensed thereto, which groups may carry up to three identical ordifferent substituents selected from the group consisting of C₁₋₆ alkyl,OH, O—(C₁₋₆ alkyl), F, Cl, and Br,

[0192] the groups defined for R^(E1) and R^(E2) may be interconnectedthrough a bond, and the groups defined for R^(E2) and R^(E3) may also beinterconnected through a bond,

[0193] R^(E2) may also denote COR^(E5) (where R^(E5) denotes OH, O—(C₁₋₆alkyl), or O—(C₁₋₃ alkylaryl)), CONR^(E6)R^(E7) (where R^(E6) and R^(E7)denote H, C₁₋₆ alkyl, or C₀₋₃ alkylaryl), or NR^(E6)R^(E7),

[0194] E may also stand for D-Asp, D-Glu, D-Lys, D-Orn, D-His, D-Dab,D-Dap, or D-Arg;

[0195] G stands for

[0196]  where _(l)G is 2, 3, 4, or 5, and one of the CH₂ groups in thering is replaceable by O, S, NH, N(C₁₋₃ alkyl), CHOH, CHO(C₁₋₃ alkyl),C(C₁₋₃ alkyl)₂, CH(C₁₋₃ alkyl), CHF, CHCl, or CF₂,

[0197]  in which

[0198]_(m)G is 0, 1, or 2,

[0199]_(n)G is 0, 1, or 2,

[0200]_(p)G is 0, 1, 2, 3, or 4,

[0201] R^(G1) denotes H, C₁₋₆ alkyl, or aryl,

[0202] R^(G2) denotes H, C₁₋₆ alkyl, or aryl,

[0203] and R^(G1) and R^(G2) may together form a —CH═CH—CH═CH— chain,

[0204] G may also stand for

[0205]  in which

[0206]_(q)G is 0, 1, or 2,

[0207]_(r)G is 0, 1, or 2,

[0208] R^(G3) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or aryl,

[0209] R^(G4) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or aryl(particularly phenyl or naphthyl);

[0210] K stands for

NH—(CH₂)_(n)K—Q^(K)

[0211]  in which

[0212]_(n)K is 0, 1, 2, or 3,

[0213] Q^(K) denotes C₂₋₆alkyl, whilst up to two CH₂ groups may bereplaced by O or S,

[0214] Q^(K) also denotes

[0215]  in which

[0216] R^(K1) denotes H, C₁₋₃ alkyl, OH, O—C(₁₋₃ alkyl), F, Cl, or Br,

[0217] R^(K2) denotes H, C₁₋₃ alkyl, O—(C₁₋₃ alkyl), F, Cl, or Br,

[0218] X^(K) denotes O, S, NH, N—(C₁₋₆ alkyl),

[0219] Y^(K) denotes

[0220] Z^(K) denotes

[0221] U^(K) denotes

[0222] V^(K) denotes

[0223] W^(K) denotes

[0224]  but in the latter case L may not be a guanidine group,

[0225]_(n)K is 0, 1, or 2,

[0226]_(p)K is 0, 1, or 2, and

[0227]_(q)K is 1 or 2;

[0228] L stands for

[0229]  in which

[0230] R^(L1) denotes H, OH, O—(C₁₋₆ alkyl), O—(CH₂)₀₋₃-phenyl,

[0231] CO—(C₁₋₆ alkyl), CO₂—(C₁₋₆ alkyl), or CO₂—(C₁₋₃ alkylaryl).

[0232] Preference is given to the following compounds of formula I

A—B—D—E—G—K—L  (I),

[0233] in which

[0234] A stands for H or H—(R^(A1))i^(A)

[0235]  in which

[0236] R^(A1) denotes

[0237]  in which R^(A4) denotes H, CH₃, or COOH,

[0238]_(i)A is 1 to 6,

[0239]_(j)A is 0, 1, or 2,

[0240]_(k)A is 2 or 3,

[0241]_(m)A is 0, 1, or 2,

[0242]_(n)A is 0, 1, or 2,

[0243] the groups R^(A1) being the same or different when _(i)A isgreater than 1;

[0244] B denotes

[0245] A—B stands for

[0246]  in which

[0247] R^(B1) denotes H or CH₂OH,

[0248] R^(B2) denotes H, NH₂, NH—COCH₃, or F,

[0249] R^(B3) denotes H, CH₃, CH₂—O—(C₁₋₄ alkyl), or COOH,

[0250] R^(B4) denotes H, C₁₋₄ alkyl, CH₂—O—(C₁₋₄ alkyl), COOH, or CHO,in which latter case intramolecular acetal formation may take place,

[0251] R^(B5) denotes H, CH₃, CH₂—O—(C₁₋₄ alkyl), or COOH,

[0252]_(k)B is 0 or 1,

[0253]_(l)B is 0, 1, 2, or 3 (_(l)B≠0 when A=R^(B1)=R^(B3)=H,_(m)B=_(k)B=0, and D is a bond),

[0254]_(m)B is 0, 1, 2, or 3,

[0255]_(n)B is 0, 1, 2, or 3,

[0256] R^(B6) denotes C₁₋₄ alkyl, phenyl, or benzyl, and

[0257] R^(B7) denotes H, C₁₋₄ alkyl, phenyl, or benzyl;

[0258] D stands for a bond or for

[0259]  in which

[0260] R^(D1) denotes H or C₁₋₄ alkyl,

[0261] R^(D2) denotes a bond or C₁₋₄ alkyl,

[0262] R^(D3) denotes

[0263] R^(D4) denotes a bond, C₁₋₄ alkyl, CO, SO₂, or —CH₂—CO;

[0264] E stands for

[0265]  in which

[0266]_(k)E is 0, 1, or 2,

[0267]_(m)E is 0, 1, 2, or 3,

[0268] R^(E1) denotes H, C₁₋₆ alkyl, or C₃₋₈ cycloalkyl, which groupsmay carry up to three identical or different substituents selected fromthe group consisting of C₁₋₆ alkyl, OH, and O—(C₁₋₆ alkyl),

[0269] R^(E2) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl (particularlyphenyl or naphthyl), heteroaryl (particularly pyridyl, furyl, orthienyl), tetrahydropyranyl, diphenylmethyl, or dicyclohexylmethyl,which groups may carry up to three identical or different substituentsselected from the group consisting of C₁₋₆ alkyl, OH, O—(C₁₋₆ alkyl), F,Cl, and Br, and may also denote CH(CF₃)₂;

[0270] R^(E3) denotes H, C₁₋₆ alkyl, or C₃₋₈ cycloalkyl, and

[0271] R^(E2) may also denote COR^(E5) (where R^(E5) denotes OH, O—C₁₋₆alkyl, or O—(C₁₋₃ alkylaryl)), CONR^(E6)R^(E7) (where R^(E6) and R^(E7)each denote H, C₁₋₆ alkyl, or C₀₋₃ alkylaryl), or NR⁶R^(E7);

[0272] E may also stand for D-Asp, D-Glu, D-Lys, D-Orn, D-His, D-Dab,D-Dap, or D-Arg;

[0273] G stands for

[0274]  where _(l)G is 2, 3, or 4, and one of the CH₂ groups in the ringis replaceable by O, S, NH, N(C₁₋₃ alkyl), CHOH, or CHO(C₁₋₃ alkyl);

[0275]  in which

[0276]_(m)G is 0, 1, or 2;

[0277]_(n)G is 0 or 1;

[0278] K stands for

NH—(CH₂)_(n)K—Q^(K)

[0279]  in which

[0280]_(n)K is 1 or 2,

[0281] Q^(K) denotes

[0282]  in which

[0283] R^(K1) denotes H, C₁₋₃ alkyl, OH, O—(C₁₋₃ alkyl), F, Cl, or Br,

[0284] R^(K2) denotes H, C₁₋₃ alkyl, O—(C₁₋₃ alkyl), F, Cl, or Br,

[0285] X^(K) denotes O, S, NH, N—(C₁₋₆ alkyl),

[0286] Y^(K) denotes

[0287] Z^(K) denotes

[0288] U^(K) denotes

[0289] and

[0290] L stands for

[0291]  in which

[0292] R^(L1) denotes H, OH, O—(C₁₋₆ alkyl), or CO₂—(C₁₋₆ alkyl).

[0293] Preferred thrombin inhibitors are compounds of formula I

A—B—D—E—G—K—L  (I),

[0294] in which

[0295] A stands for H or H—(R^(A1))i^(A) in which

[0296] R^(A1) denotes

[0297]  in which R^(A4) denotes H or COOH,

[0298]_(i)A is 1 to 6,

[0299]_(j)A is 0 or 1,

[0300]_(k)A is 2 or 3,

[0301]_(n)A is 1 or 2,

[0302] the groups R^(A1) being the same or different when _(i)A isgreater than 1;

[0303] B denotes

[0304]  in which

[0305] R^(B3) denotes H, CH₃, or COOH,

[0306] R^(B4) denotes H, CH₃, COOH, or CHO, in which latter caseintramolecular acetal formation may take place,

[0307]_(k)B is 0 or 1,

[0308]_(l)B is 1, 2, or 3,

[0309]_(m)B is 0, 1, 2, or 3, and

[0310]_(n)B is 1, 2, or 3;

[0311] D stands for a bond;

[0312] E stands for

[0313]  in which

[0314]_(m)E is 0 or 1,

[0315] R^(E2) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl,diphenylmethyl, or dicyclohexylmethyl, which groups may carry up tothree identical or different substituents selected from the groupconsisting of C₁₋₄ alkyl, OH, O—CH₃, F, and Cl;

[0316] G stands for

[0317]  where _(l)G is 2, 3, or 4 and one of the CH₂ groups in the ringis replaceable by O, S, NH, or N(C₁₋₃ alkyl),

[0318]  in which

[0319]_(n)G is 0 or 1;

[0320] K stands for

NH—CH₂—Q^(K)

[0321]  in which

[0322] Q^(K) denotes

[0323]  in which

[0324] R^(K1) denotes H, CH₃, OH, O—CH₃, F, or Cl,

[0325] X^(K) denotes O, S, NH, N—CH₃,

[0326] Y^(K) denotes

[0327] Z^(K) denotes

[0328] L stands for

[0329]  in which

[0330] R^(L1) denotes H, OH, or CO₂—(C₁₋₆ alkyl).

[0331] Preferred complement inhibitors are compounds of formula I

A—B—D—E—G—K—L  (I),

[0332] in which

[0333] A stands for H or H—(R^(A1))i^(A) in which

[0334] R^(A1) denotes

[0335]  in which R^(A4) denotes H or COOH,

[0336]_(i)A is 1 to 6,

[0337]_(j)A is 0 or 1,

[0338]_(k)A is 2 or 3,

[0339]_(n)A is 1 or 2,

[0340] the groups R^(A1) being the same or different when _(i)A isgreater than 1;

[0341] B denotes

[0342] A—B stands for

[0343]  in which

[0344] R^(B3) denotes H, CH₃, or COOH,

[0345] R^(B4) denotes H, CH₃, COOH, or CHO, in which latter caseintramolecular acetal formation may take place,

[0346]_(k)B is 0 or 1,

[0347]_(l)B is 1, 2, or 3,

[0348]_(m)B is 0, 1, 2, or 3,

[0349]_(n)B is 1, 2, or 3,

[0350] R^(B6) denotes C₁₋₄ alkyl, phenyl, or benzyl, and

[0351] R^(B7) denotes H, C₁₋₄ alkyl, phenyl, or benzyl,

[0352] D stands for

[0353]  in which

[0354] R^(D1) denotes H or C₁₋₄ alkyl,

[0355] R^(D2) denotes a bond or C₁₋₄ alkyl,

[0356] R^(D3) denotes

[0357]  in which

[0358] R^(D4) denotes a bond, C₁₋₄ alkyl, CO, SO₂, or —CH₂—CO, and

[0359] R^(D6) denotes H or CH₃;

[0360] E stands for

[0361]  in which

[0362]_(m)E is 0 or 1,

[0363] R^(E2) denotes H, C₁₋₆ alkyl, or C₃₋₈ cycloalkyl, which groupsmay carry up to three identical or different substituents selected fromthe group consisting of C₁₋₄ alkyl, OH, O—CH₃, F, and Cl;

[0364] G stands for

[0365]  where _(l)G is 2, 3, or 4 and one of the CH₂ groups in the ringis replaceable by O, S, NH, or —N(C₁₋₃ alkyl), or

[0366]  in which

[0367]_(n)G is 0 or 1;

[0368] K stands for

NH—CH₂—Q^(K)

[0369]  in which

[0370] Q^(K) denotes

[0371]  in which

[0372] R^(K1) denotes H, CH₃, OH, O—CH₃, F, or Cl,

[0373] X^(K) denotes O, S, NH, N—CH₃,

[0374] Y^(K) denotes

[0375] Z^(K) denotes

[0376] L stands for

[0377]  in which

[0378] R^(L1) denotes H, OH, or CO₂—(C₁₋₆ alkyl).

[0379] Particularly preferred thrombin inhibitors are compounds offormula I

A—B—D—E—G—K—L  (I),

[0380] in which

[0381] A stands for H or H—(R^(A1))i^(A) in which

[0382] R^(A1) denotes

[0383]  in which _(i)A is 1 to 6,

[0384]_(j)A is 0 or 1,

[0385]_(i)A is 1 or 2,

[0386] the groups R^(A1) being the same or different when _(i)A isgreater than 1;

[0387] B denotes

[0388]  in which

[0389]_(l)B is 1, 2, or 3,

[0390]_(m)B is 1 or 2,

[0391] D stands for a bond,

[0392] E stands for

[0393]  in which

[0394]_(m)E is 0 or 1,

[0395] R^(E2) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl,diphenylmethyl, or dicyclohexylmethyl,

[0396] building block E preferably exhibiting D configuration,

[0397] G stands for

[0398] building block G preferably exhibiting L configuration;

[0399] K stands for

NH—CH₂—Q^(K)

[0400]  in which

[0401] Q^(K) denotes

[0402] and

[0403] L stands for

[0404]  in which

[0405] R^(L1) denotes H, OH, or CO₂—(C₁₋₆ alkyl).

[0406] Particularly preferred complement inhibitors are compounds offormula I

A—B—D—E—G—K—L  (I),

[0407] in which

[0408] A stands for H or H—(R^(A1))i^(A) in which

[0409] R^(A1) denotes

[0410]  in which R^(A4) denotes H or COOH,

[0411]_(i)A is 1 to 6,

[0412]_(j)A is 0 or 1,

[0413]_(k)A is 2 or 3,

[0414]_(n)A is 1 or 2,

[0415] the groups R^(A1) being the same or different when _(i)A isgreater than 1;

[0416] B denotes

[0417] A—B stands for

[0418]  in which

[0419] R^(B3) denotes H, CH₃, or COOH,

[0420] R^(B4) denotes H, CH₃, COOH, or CHO, in which latter caseintramolecular acetal formation may take place,

[0421]_(k)B is 0 or 1,

[0422]_(l)B is 1, 2, or 3,

[0423]_(m)B is 0, 1, 2, or 3,

[0424]_(n)B is 1, 2, or 3,

[0425] R^(B6) denotes C₁₋₄ alkyl, phenyl, or benzyl, and

[0426] R^(B7) denotes H, C₁₋₄ alkyl, phenyl, or benzyl,

[0427] D stands for

[0428]  in which

[0429] R^(D1) denotes H,

[0430] R^(D2) denotes a bond or C₁₋₄ alkyl,

[0431] R^(D3) denotes

[0432] R^(D4) denotes a bond, C₁₋₄ alkyl, CO, SO₂, or —CH₂—CO, and

[0433] E stands for

[0434]  in which

[0435]_(m)E is 0 or 1,

[0436] R^(E2) denotes H, C₁₋₆ alkyl, or C₃₋₈ cycloalkyl, which groupsmay carry up to three identical or different substituents selected fromthe group consisting of F and Cl;

[0437] G stands for

[0438]  where _(l)G is 2

[0439]  in which

[0440]_(n)G is 0,

[0441] K stands for

NH—CH₂Q^(K)

[0442]  in which

[0443] Q^(K) denotes

[0444]  in which

[0445] X^(K) denotes S,

[0446] Y^(K) denotes ═CH—, or ═N—,

[0447] Z^(K) denotes ═CH—, or ═N—, and

[0448] L stands for

[0449]  in which

[0450] R^(L1) denotes H or OH.

[0451] Preferred building blocks A—B are: D-Fructo

D-Turano-

3-O-Methyl- D-glucopyrano-

D-Galacturo-

Glucuronamo-

N-Acetyl- neuraminic

D-Digitoxo

Maltotrio-

Maltotetrao-

2-Deoxy-D- galacto

2-Acetamido- 2-deoxy-3-O- (delta-d-galacto- pyranosyl)-D- glucopyrano

D-Mannoheptulo

alpha-Spphoro-

N-Acetyl-D- Mannosami-

6-Acetamido-6- Deoxy-alpha- D-Glucopyrano-

3-O-Beta-D- Galatopyranosyl- D-Arabino-

D-Glucohepto-

Nigero-

D-Glucoheptulo-

Xylotrio-

2-Acetamido-2- Deoxy-6-O-(beta- D-galactopyrano- syl)-D-glucopyrano-

4-O-(4-O-[6-O- alpha-D-gluco- pyranosyl-alpha- glucopyranosyl]-alpha-D-glucopyr-

2-Acetamido-6-O- (2-acetamido-2- deoxy-beta-D- glucopyranosyl)-2-deoxy-D- glucopyran-

6-O-(2-Acetamido- 2-deoxy-beta-D- glucopyranosyl)-D- galactopyrano-

2-Acetamido-2- deoxy-4-O-([4-O- beta-D-galacto- pyranosyl]-beta-D-galactopyranosyl)

N-Acetyl-D- glucosamin-

2-Fluoro-2-deoxy- D-galactopyrano-

6-Deoxy-D-gluco-

L-Allo-

3-O-Methylgluco-

D-Allo-

6-Fluoro-6- deoxy-D- galactopyrano-

D-Gluco-

Dextro-

N-Acetyl- lactosamin-

L-Galacto-

L-Gluco-

4-O-alpha-D- galactopyrano- syl-D-galacto- pyrano-

2-Acetamido-2- deoxy-4-O([4- O-beta-D- galactopyrano- syl]-beta-D-galactopyranosyl)-

6-Fluoro-6-deoxy- D-glucopyrano-

L-Lyxo-

L-Manno-

D-Manno-

N-Acetyl-D- glucosamin-

D-Lyxo-

D-Lacto-

Maltoheptao-

D-Talo-

L-Talo-

Neohesperido-

N-Acetyl-D- galactosamin-

Isomalto-

Beta-Malto-

L-Fructo-

6-O-Methyl- D-galactopyrano-

2-Deoxy-D- Ribohexopyrano-

Alpha-D-Kojibio-

2-O-Methyl-D-xylo-

L-Fluco-

6-O-Beta-D- galactopyrano- syl-D-galacto-

L-Gulo-

D-Gulo-

D-Ido-

L-Ido-

(4-O-(4-O-Beta- D-galacto- pyranosyl)-beta- D-galacto- pyranosyl)-D-glucopyrano-

D-Cellotrio-

Laminaribio-

3-O-alpha-D- mannopyrano-syl- D-mannopyrano-

4-O-beta- Galacto- pyranosyl- D-mannopyrano-

Isomaltotrio-

D-Galacturonic-

L-Rhamno-

D-Altro-

N,N′-Diacetyl- chitobio-

D-Glucuronic-

(+)-Digitoxo-

6-O-[2-Aceta- mido-2-deoxy-4- O-(beta-D-galacto- pyranosyl)-beta-D-gluco- pyranosyl]-D-

4-O-(6-O-[Aceta- mido-2-deoxy- beta-D-gluco- pyranosyl]-beta- D-galacto-pyranosyl)-

D-Cellotetrao-

Digalacturonic-

2′-Fucosyllacto-

3-Fucosyllacto-

Lacto-N-Tetrao-

4-O-(2-O- Methyl-beta-D- galactopyrano- syl)-D-gluco- pyrano-

A-Lactulo-

Maltohexao-

L-Allo-

3-Deoxy-D-Gluco-

Isomaltotetrao-

Xylobio-

Maltopentao-

Sophoro-

D-Lacto-

2-Acetamido-2- deoxy-3-O- (alpha-L-fuco- pyranosyl)-D- glucopyrano-

2-Acetamido-2- deoxy-4-O- (alpha-L-Fuco- pyranosyl)-D- glucopyrano-

D-Mannohepto-

Epilacto-

Leucro-

A-Lactin-

Gantoobio-

D-Melibio-

Dimer-N-acetyl- galactosamin-

2-O-alpha-L- Fucosyl-D-galacto

Lactodifuco- tetrrao-

6-O-alpha-D- Mannopyranosyl- D-mannopyrano-

2-Acetamido-2- deoxy-6-O-(beta- D-galacto- pyranosyl)-D- galactopyrano-

D-Rhamno-

D-Cellohexo-

L-Altro-

3-O-[2-Aceta- mido-2-deoxy- beta-D-gluco- pyranosyl]-D- mannopyrano-

2-Deoxy-2- fluoro-D-manno-

4-Deoxy-L-fuco-

2-O-(alpba-D- galacto- pyranosyl)-D- galacto-

3-O-(alpha- D-Galacto- pyranosyl)-D- galacto-

D-Galacto-

Globotrio-

2-Acetamido-2- deoxy-4-O-beta- D-galacto- pyranosyl-D- mannopyrano-

2-Acetamido-2- deoxy-4-O-(beta- D-manno- pyranosyl)-D- glucopyrano-

4-O-beta-D- galacto- pyranosyl-D- galactopyrano-

4-O-(3-O-alpha- D-Galacto- pyranosyl-beta- D-galacto- pyranosyl)-D-galactopyrano-

A1-3, B1-4, A1-3 Galactotetrao-

2-O-alpha-D- Mannopyranosyl- D-mannopyrano-

4-O-alpla-D- Mannopyranosyl- D-mannopyrano-

2-O-(2-Aceta- mido-2-deoxy- beta-D-gluco- pyranosyl)- D-manno-

3-O-(alpha-L- Fucopyranosyl)- D-galacto-

4-O-(alpha-L- Fucopyranosyl)- D-galacto-

2′-Fucosyl-N- acetallactos-ami

Laminaritrio-

Laminaritetrao-

Laminaripentao-

Laminarihexao-

Lacto-N-bio

A1-2-Mannobio-

A1-3,A1-6- Mannotrio-

A1-3,A1-6- Mannopentao-

2-Acetamido-2- deoxy-3-O- methyl-D- glucopyranosi-

Fucose alpha A1,2-galactose- beta A1,4-N- acetylglucosami-

Fucose alpha 1,6-N-acetylglu- cosami-

Galactose beta 1,6-N-acetyl- glucosami-

D-Ribulo-

D-Threo-

Arabinic AC-

Lactulo-

L-Xylulo-

D-Xylulo-

D-Fructo-

L-Threo-

5-Deoxy-D-xylo- furano-

2-Fluoro-2- deoxy-D-arabino-

Palatino-

2-Deoxy-L-ribo-

Maltulo-

Trehalulo-

D-Arabino-

L-Arabino-

D-Erythro-

L-Glycer-

L-Erythro-

D-Glycer-

L-Ribo-

D-Ribo-

D-Fuco-

D-Cellobio-

5-Deoxy-L-arabino-

D-Xylo-

L-Xylo-

Cellopentao-

Pano-

Rutino-

Beta-Gentiobio-

6-Deoxy-L-talo-

L-Iduronic-

L-Glycerol-L- galactohepto-

L-Glycero-D- glucohepto-

D-Lacta-

Gluconic-

5-Ketogluconic-

Heptagluconic-

Lactobionic-

D-Xylonic-

Arabic-

[0452] The term “C_(1-x) alkyl” denotes any linear or branched alkylchain containing from 1 to x carbons.

[0453] The term “C₃₋₈ cycloalkyl” denotes carbocyclic saturated radicalscontaining from 3 to 8 carbons.

[0454] The term “aryl” stands for carbocyclic aromatics containing from6 to 14 carbons, particularly phenyl, 1-naphthyl, and 2-naphthyl.

[0455] The term “heteroaryl” stands for five-ring and six-ring aromaticscontaining at least one heteroatom N, O, or S, and particularly denotespylidyl, thienyl, furyl, thiazolyl, and imidazolyl; two of the aromaticrings may be condensed, as in indole, N—(C₁₋₃ alkyl)indole,benzothiophene, benzothiazole, benzimidazole, quinoline, andisoquinoline.

[0456] The term “C_(x-y) alkylaryl” stands for carbocyclic aromaticsthat are linked to the skeleton through an alkyl group containing x, x+1. . . y−1, or y carbons.

[0457] The compounds of formula I can exist as such or be in the form oftheir salts with physiologically acceptable acids. Examples of suchacids are: hydrochloric acid, citric acid, tartaric acid, lactic acid,phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleicacid, fumaric acid, succinic acid, hydroxysuccinic acid, sulfuric acid,glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronicacid, oxalic acid, ascorbic acid, and acetylglycine.

[0458] The novel compounds of formula I are competitive inhibitors ofthrombin or the complement system, especially C1s, and also C1r.

[0459] The compounds of the invention can be administered inconventional manner orally or parenterally (subcutaneously,intravenously, intramuscularly, intraperitoneally, or rectally).Administration can also be carried out with vapors or sprays applied tothe postnasal space.

[0460] The dosage depends on the age, condition, and weight of thepatient, and also on the method of administration used. Usually thedaily dose of the active component per person is between approximately10 and 2000 mg for oral administration and between approximately 1 and200 mg for parenteral administration. These doses can take the form offrom 2 to 4 single doses per day or be administered once a day as depot.

[0461] The compounds can be employed in commonly used galenic solid orliquid administration forms, eg, as tablets, film tablets, capsules,powders, granules, dragees, suppositories, solutions, ointments, creams,or sprays. These are produced in conventional manner. The activesubstances can be formulated with conventional galenic auxiliaries, suchas tablet binders, fillers, preserving agents, tablet bursters, flowregulators, plasticizers, wetters, dispersing agents, emulsifiers,solvents, retarding agents, antioxidants, and/or fuel gases (cf H.Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart,1978). The resulting administration forms normally contain the activesubstance in a concentration of from 0.1 to 99 wt %.

[0462] The term “prodrugs” refers to compounds which are converted tothe pharmacologically active compounds of the general formula I in vivo(eg, first pass metabolisums).

[0463] Where, in the compounds of formula I, R^(L1) is not hydrogen, therespective substances are prodrugs from which the free amidine orguanidine compounds are formed under in vivo conditions. If esterfunctions are present in the compounds of formula I, these compounds canact, in vivo, as prodrugs, from which the corresponding carboxylic acidsare formed.

[0464] Apart from the substances mentioned in the examples, thefollowing compounds are very particularly preferred and can be producedaccording to said manufacturing instructions: 1.L-Glycer-D-Cha-Pro-NH-4-amb 2. D-Glycer-D-Cha-Pro-NH-4-amb 3.L-Erythro-D-Cha-Pro-NH-4-amb 4. D-Erythro-D-Cha-Pro-NH-4-amb 5.L-Threo-D-Cha-Pro-NH-4-amb 6. D-Threo-D-Cha-Pro-NH-4-amb 7.L-Arabino-D-Cha-Pro-NH-4-amb 8. D-Arabino-D-Cha-Pro-NH-4-amb 9.L-Ribo-D-Cha-Pro-NH-4-amb 10. D-Ribo-D-Cha-Pro-NH-4-amb 11.2-Deoxy-L-Ribo-D-Cha-Pro-NH-4-amb 12. D-Fuco-D-Cha-Pro-NH-4-amb 13.D-Cellobio-D-Cha-Pro-NH-4-amb 14. D-Xylo-D-Cha-Pro-NH-4-amb 15.L-Xylo-D-Cha-Pro-NH-4-amb 16. Cellopentao-D-Cha-Pro-NH-4-amb 17.D-Fructo-D-Cha-Pro-NH-4-amb 18. Maltotrio-D-Cha-Pro-NH-4-amb 19.Maltotetrao-D-Cha-Pro-NH-4-amb 20. Glucohepto-D-Cha-Pro-NH-4-amb 21.L-Allo-D-Cha-Pro-NH-4-amb 22. D-Allio-D-Cha-Pro-NH-4-amb 23.D-Gluco-D-Cha-Pro-NH-4-amb 24. L-Gluco-D-Cha-Pro-NH-4-amb 25.D-Manno-D-Cha-Pro-NH-4-amb 26. L-Manno-D-Cha-Pro-NH-4-amb 27.L-Galacto-D-Cha-Pro-NH-4-amb 28. Dextro-D-Cha-Pro-NH-4-amb 29.L-Lyxo-D-Cha-Pro-NH-4-amb 30. D-Lyxo-D-Cha-Pro-NH-4-amb 31.D-Lacto-D-Cha-Pro-NH-4-amb 32. D-Talo-D-Cha-Pro-NH-4-amb 33.L-Talo-D-Cha-Pro-NH-4-amb 34. beta-Malto-D-Cha-Pro-NH-4-amb 35.L-Fuco-D-Cha-Pro-NH-4-amb 36. L-Gulo-D-Cha-Pro-NH-4-amb 37.D-Gulo-D-Cha-Pro-NH-4-amb 38. L-ldo-D-Cha-Pro-NH-4-amb 39.D-ldo-D-Cha-Pro-NH-4-amb 40. D-Cellotrio-D-Cha-Pro-NH-4-amb 41.D-Galacturonic-D-Cha-Pro-NH-4-amb 42. D-Glucuronic-D-Cha-Pro-NH-4-amb43. L-Rhamno-D-Cha-Pro-NH-4-amb 44. D-Cellotetrao-D-Cha-Pro-NH-4-amb 45.Maltohexao-D-Cha-Pro-NH-4-amb 46. Maltopentao-D-Cha-Pro-NH-4-amb 47.Xylobio-D-Cha-Pro-NH-4-amb 48. D-Lacto-D-Cha-Pro-NH-4-amb 49.D-Melibio-D-Cha-Pro-NH-4-amb 50. Gentobio-D-Cha-Pro-NH-4-amb 51.D-Rhamno-D-Cha-Pro-NH-4-amb 52. L-Altro-D-Cha-Pro-NH-4-amb 53.D-Galacto-D-Cha-Pro-NH-4-amb 54. L-Glycer-D-Chg-Ace-NH-4-amb 55.D-Glycer-D-Chg-Ace-NH-4-amb 56. L-Erythro-D-Chg-Ace-NH-4-amb 57.D-Erythro-D-Chg-Ace-NH-4-amb 58. L-Threo-D-Chg-Ace-NH-4-amb 59.D-Threo-D-Chg-Ace-NH-4-amb 60. L-Arabino-D-Chg-Ace-NH-4-amb 61.D-Arabino-D-Chg-Ace-NH-4-amb 62. L-Ribo-D-Chg-Ace-NH-4-amb 63.D-Ribo-D-Chg-Ace-NH-4-amb 64. 2-Deoxy-L-Ribo-D-Chg-Ace-NH-4-amb 65.D-Fuco-D-Chg-Ace-NH-4-amb 66. D-Cellobio-D-Chg-Ace-NH-4-amb 67.D-Xylo-D-Chg-Ace-NH-4-amb 68. L-Xylo-D-Chg-Ace-NH-4-amb 69.Cellopentao-D-Chg-Ace-NH-4-amb 70. D-Fructo-D-Chg-Ace-NH-4-amb 71.Maltotrio-D-Chg-Ace-NH-4-amb 72. Maltotetrao-D-Chg-Ace-NH-4-amb 73.Glucohepto-D-Chg-Ace-NH-4-amb 74. L-Allo-D-Chg-Ace-NH-4-amb 75.D-Allo-D-Chg-Ace-NH-4-amb 76. L-Gluco-D-Chg-Ace-NH-4-amb 77.D-Manno-D-Chg-Ace-NH-4-amb 78. L-Manno-D-Chg-Ace-NH-4-amb 79.L-Galacto-D-Chg-Ace-NH-4-amb 80. Dextro-D-Chg-Ace-NH-4-amb 81.L-Lyxo-D-Chg-Ace-NH-4-amb 82. D-Lyxo-D-Chg-Ace-NH-4-amb 83.D-Lacto-D-Chg-Ace-NH-4-amb 84. D-Talo-D-Chg-Ace-NH-4-amb 85.L-Talo-D-Chg-Ace-NH-4-amb 86. L-Fuco-D-Chg-Ace-NH-4-amb 87.L-Gulo-D-Chg-Ace-NH-4-amb 88. D-Gulo-D-Chg-Ace-NH-4-amb 89.L-Ido-D-Chg-Ace-NH-4-amb 90. D-Ido-D-Chg-Ace-NH-4-amb 91.D-Cellotrio-D-Chg-Ace-NH-4-amb 92. D-Galacturonic-D-Chg-Ace-NH-4-amb 93.D-Glucuronic-D-Chg-Ace-NH-4-amb 94. L-Rhamno-D-Chg-Ace-NH-4-amb 95.D-Cellotetrao-D-Chg-Ace-NH-4-amb 96. Maltohexao-D-Chg-Ace-NH-4-amb 97.Maltopentao-D-Chg-Ace-NH-4-amb 98. Xylobio-D-Chg-Ace-NH-4-amb 99.D-Lacto-D-Chg-Ace-NH-4-amb 100. D-Melibio-D-Chg-Ace-NH-4-amb 101.Gentobio-D-Chg-Ace-NH-4-amb 102. D-Rhamno-D-Chg-Ace-NH-4-amb 103.L-Altro-D-Chg-Ace-NH-4-amb 104. D-Galacto-D-Chg-Ace-NH-4-amb 105.L-Glycer-D-Cha-Pyr-NH-3-(6-am)-pico 106.D-Glycer-D-Cha-Pyr-NH-3-(6-am)-pico 107.L-Erythro-D-Cha-Pyr-NH-3-(6-am)-pico 108.D-Erythro-D-Cha-Pyr-NH-3-(6-am)-pico 109.L-Threo-D-Cha-Pyr-NH-3-(6-am)-pico 110.D-Threo-D-Cha-Pyr-NH-3-(6-am)-pico 111.L-Arabino-D-Cha-Pyr-NH-3-(6-am)-pico 112.D-Arabino-D-Cha-Pyr-NH-3-(6-am)-pico 113.L-Ribo-D-Cha-Pyr-NH-3-(6-am)-pico 114. D-Ribo-D-Cha-Pyr-NH-3-(6-am)-pico115. 2-Deoxy-L-Ribo-D-Cha-Pyr-NH-3-(6-am)-pico 116.D-Fuco-D-Cha-Pyr-NH-3-(6-am)-pico 117.D-Cellobio-D-Cha-Pyr-NH-3-(6-am)-pico 118.D-Xylo-D-Cha-Pyr-NH-3-(6-am)-pico 119. L-Xylo-D-Cha-Pyr-NH-3-(6-am)-pico120. Cellopentao-D-Cha-Pyr-NH-3-(6-am)-pico 121.D-Fructo-D-Cha-Pyr-NH-3-(6-am)-pico 122.Maltotrio-D-Cha-Pyr-NH-3-(6-am)-pico 123.Maltotetrao-D-Cha-Pyr-NH-3-(6-am)-pico 124.Glucohepto-D-Cha-Pyr-NH-3-(6-am)-pico 125.L-Allo-D-Cha-Pyr-NH-3-(6-am)-pico 126. D-Allo-D-Cha-Pyr-NH-3-(6-am)-pico127. D-Gluco-D-Cha-Pyr-NH-3-(6-am)-pico 128.L-Gluco-D-Cha-Pyr-NH-3-(6-am)-pico 129.D-Manno-D-Cha-Pyr-NH-3-(6-am)-pico 130.L-Manno-D-Cha-Pyr-NH-3-(6-am)-pico 131.L-Galacto-D-Cha-Pyr-NH-3-(6-am)-pico 132.Dextro-D-Cha-Pyr-NH-3-(6-am)-pico 133. L-Lyxo-D-Cha-Pyr-NH-3-(6-am)-pico134. D-Lyxo-D-Cha-Pyr-NH-3-(6-am)-pico 135.D-Lacto-D-Cha-Pyr-NH-3-(6-am)-pico 136.D-Talo-D-Cha-Pyr-NH-3-(6-am)-pico 137. L-Talo-D-Cha-Pyr-NH-3-(6-am)-pico138. beta-Malto-D-Cha-Pyr-NH-3-(6-am)-pico 139.L-Fuco-D-Cha-Pyr-NH-3-(6-am)-pico 140. L-Gulo-D-Cha-Pyr-NH-3-(6-am)-pico141. D-Gulo-D-Cha-Pyr-NH-3-(6-am)-pico 142.L-ldo-D-Cha-Pyr-NH-3-(6-am)-pico 143. D-Ido-D-Cha-Pyr-NH-3-(6-am)-pico144. D-Cellotrio-D-Cha-Pyr-NH-3-(6-am)-pico 145.D-Galacturonic-D-Cha-Pyr-NH-3-(6-am)-pico 146.D-Glucuronic-D-Cha-Pyr-NH-3-(6-am)-pico 147.L-Rhamno-D-Cha-Pyr-NH-3-(6-am)-pico 148.D-Cellotetrao-D-Cha-Pyr-NH-3-(6-am)-pico 149.Maltohexao-D-Cha-Pyr-NH-3-(6-am)-pico 150.Maltopentao-D-Cha-Pyr-NH-3-(6-am)-pico 151.Xylobio-D-Cha-Pyr-NH-3-(6-am)-pico 152.D-Lacto-D-Cha-Pyr-NH-3-(6-am)-pico 153.D-Melibio-D-Cha-Pyr-NH-3-(6-am)-pico 154.Gentobio-D-Cha-Pyr-NH-3-(6-am)-pico 155.D-Rhamno-D-Cha-Pyr-NH-3-(6-am)-pico 156.L-Altro-D-Cha-Pyr-NH-3-(6-am)-pico 157.D-Galacto-D-Cha-Pyr-NH-3-(6-am)-pico 158.L-Erythro-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 159.D-Threo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 160.L-Ribo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 161.D-Ribo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 162.2-Deoxy-L-Ribo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 163.D-Fuco-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 164.D-Cellobio-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 165.D-Xylo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 166.L-Xylo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 167.Cellopentao-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 168.D-Fructo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 169.Maltotrio-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 170.Maltotetrao-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 171.Glucohepto-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 172.L-Allo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 173.D-Allo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 174.D-Gluco-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 175.L-Gluco-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 176.D-Manno-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 177.L-Manno-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 178.L-Galacto-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 179.Dextro-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 180.L-Lyxo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 181.D-Lyxo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 182.D-Lacto-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 183.D-Talo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 184.L-Talo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 185.beta-Maltro-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 186.L-Fuco-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 187.L-Gulo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 188.D-Gulo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 189.L-Ido-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 190.D-ldo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 191.D-Cellotrio-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 192.D-Galacturonic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 193.D-Glucuronic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 194.D-Cellotetrao-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 195.Maltohexao-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 196.Maltopentao-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 197.Xylobio-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 198.D-Lacto-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 199.Gentobio-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 200.D-Rhamno-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 201.L-Altro-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 202.D-Galacto-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 203.D-Galacturo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 205.D-Glucohepto-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 206.L-Allo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 207.D-Allo-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 208.D-Gluco-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 209.D-Galacto-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 210.L-Gluco-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 211.L-Manno-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 212.D-Manno-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 213.D-Cellotrio-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 214.D-Cellobio-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 215.D-Glucuronic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 216. ArabinicAC-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 217.L-lduronic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 218.Gluconlc-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 219.Heptagluconic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 220.Lactobionic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 221.D-Xylonic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 222.Arabic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 223.Phenyl-beta-D-Glucuronic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 224.Methyl-beta-D-Glucuronic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 225.D-quinic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 226.Phenyl-alpha-iduronic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 227.Digalacturonlc-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 228.Trigalacturonic-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 229.3,4,5-Trihydroxy-6-hydroxymethy-tetrahydropyranyl(2)-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 230.3-Acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyanyl(2)-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 231.D-Galacturo-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 232.D-Glucohepto-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 233.L-Allo-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 234.D-Allo-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 235.D-Gluco-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 236.D-Galacto-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 237.L-Gluco-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 238.L-Manna-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 239.D-Manno-NH-cyclohexyl-O-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 240.D-Cellotrio-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 241.D-Cellobio-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 242.D-Glucuronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 243.Arabinic AC-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 244.L-Iduronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 245.Gluconic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 246.Heptagluconic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 247.Lactoblonlc-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 248.D-Xylonic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 249.Arabic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 250.Pheny-beta-D-Glucuronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz251.Methyl-beta-D-Glucuronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz252. D-quinic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 253.Phenyl-alpha-iduronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz254. Digalacturonic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz255. Trigalacturonic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz256.3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 257.3-acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 258.D-Galacturo-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 259.D-Glucohepto-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 260.L-Allo-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 261.D-Allo-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 262.D-Gluco-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 263.D-Galacto-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 264.L-Gluco-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 265.L-Manno-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 266.D-Manno-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 267.D-Cellotrio-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 268.D-Cellobio-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 269.D-Glucuronic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 270.Arabinic AC-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 271.L-lduronic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 272.Gluconic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 273.Heptagluconic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 274.Lactobionic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 275.D-Xylonic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 276.Arabic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 277.Phenyl-beta-D-Glucuronic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz278.Methyl-beta-D-Glucuronic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz279. D-quinic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 280.Phenyl-alpha-iduronic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz281. Digalacturonlc-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz282. Trigalacturonic-NH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz283.3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CONH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 284.3-Acetamldo-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CONH-CH₂-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 285.D-Galacturo-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 286.D-Glucohepto-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 287.L-Allo-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 288.D-Allo-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 289.D-Gluco-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 290.D-Galacto-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 291.L-Gluco-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 292.L-Manno-NH-CH₂-p-phenyl-CH₂-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 293.D-Manno-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 294.D-Cellotrio-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 295.D-Cellobio-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 296.D-Glucuronic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 297.Arabinic AC-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 298.L-lduronlc-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 299.Gluconic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 300.Heptagluconic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz301. Lactobionic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz302. D-Xylonic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz303. Arabic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 304.Phenyl-beta-D-Glucuronic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz305.Methyl-beta-D-Glucuronic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz306. D-quinic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz307.Phenyl-alpha-Iduronic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz308.Digalacturonic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz309.Trigalacturonic-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz310.3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 311.3-Acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-CH₂-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 312.D-Galacturo-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 313.D-Glucohepto-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 314.L-Allo-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 315.D-Allo-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 316.D-Gluco-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 317.D-Galacto-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 318.L-Gluco-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 319.L-Manno-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 320.D-Manno-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 321.D-Cellotrio-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 322.D-Cellobio-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 323.D-Glucuronic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 324.Arabinic AC-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 325.L-lduronic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 326.Gluconic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 327.Heptagluconic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 328.Lactobionlc-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 329.D-Xylonic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 330.Arabic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 331.Phenyt-beta-D-Glucuronic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz332.Methyl-beta-D-Glucuronlc-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz333. D-quinic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 334.Phenyl-alpha-Iduronic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz335. Digalacturonlc-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz336. Trigalacturonic-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz337.3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydropyrany[(2)-CO-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 338.3-Acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-p-phenyl-CH₂-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 339.D-Galacturo-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 340.D-Glucohepto-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 341.L-Allo-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 342.D-Allo-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 343. DGluco-NH-p-henyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 344.D-Galacto-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 345.L-Gluco-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 346.L-Manno-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 347.D-Manno-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 348.D-Cellotrio-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 349.D-Cellobio-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 350.D-Glucuronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 351.Arabinic AC-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 352.L-lduronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 353.Gluconic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 354.Heptagluconic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 355.Lactobionic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 356.D-Xylonic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 357.Arabic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 358.Phenyl-beta-D-Glucuronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz359.Methyl-beta-D-Glucuronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz360. D-quinlc-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 361.Phenyl-alpha-iduronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz362. Digalacturonic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 363.3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 364.3-acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 365.Trlgalacturonic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH₂-2-(4-am)-thiaz 366.L-Glycer-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 367.D-Glycer-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 368.L-Erythro-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 369.D-Erythro-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 370.L-Threo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 371.D-Threo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 372.L-Arabino-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 373.D-Arabino-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 374.L-Ribo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 375.D-Rlbo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 376.2-Deoxy-L-Ribo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 377.D-Fuco-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 378.D-Xylo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 379.L-Xylo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 380.Cellopentao-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 381.D-Fructo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 382.Maltotrio-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 383.Maltotetrao-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 384.Glucohepto-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 385.L-Allo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 386.D-Allo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 387.L-Gluco-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 388.D-Manno-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 389.L-Manno-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 390.L-Galacto-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 391.Dextro-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 392.L-Lyxo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 393.D-Lyxo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 394.D-Lacto-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 395.D-Talo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 396.L-Talo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 397.beta-Malto-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 398.L-Fuco-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 399.L-Gulo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 400.D-Gulo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 401.L-ldo-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 402.D-Ido-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 403.D-Celotrio-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 404.D-Gatacturonic-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 405.L-Rhamno-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 406.D-Cellotetrao-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 407.Maltopentao-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 408.Xylobio-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 409.D-Lacto-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 410.D-Melibio-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 411.Gentobio-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 412.D-Rhamno-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 413.L-Altro-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph 414.D-Galacto-D-Chg-Pyr-NH-CH₂-5-(3-am)-thioph

[0465] List of Abbreviations: Abu: 2-aminobutyric acid AIBN:azobisisobutyronitrile Ac: acetyl Acpc: 1-aminocyclopentane-1-carboxylicacid Achc: 1-aminocyclohexane-1-carboxylic acid Aib: 2-aminoisobutyricacid Ala: alanine b-Ala: beta-alanine (3-aminopropionic acid) am:amidino amb: amidinobenzyl 4-amb: 4-amidinobenzyl (p-amidinobenzyl) Arg:Arginine Asp: aspartic acid Aze: azetidine-2-carboxylic acid Bn: benzylBoc: tert-butyloxycarbonyl Bu: butyl Cbz: carbobenzoxy Cha:cyclohexylalanine Chea: cycloheptylalanine Cheg: cycloheptylglycine Chg:cyclohexylglycine Cpa: cyclopentylalanine Cpg: cyclopentylglycine d:doublet Dab: 2,4-diaminobutyric acid Dap: 2,3-diaminopropionic acid DC:thin-layer chromatography DCC: dicyclohexylcarbodiimide Dcha:dicyclohexylamine DCM: dichloromethane Dhi-1-COOH:2,3-dihydro-1H-isoindole-1-carboxylic acid DMF: dimethylformamide DIPEA:diisopropylethylamine EDC:N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide Et: ethyl Eq: equivalentGly: glycine Glu: glutamic acid fur: furan guan: guanidino ham:hydroxyamidino HCha: homocyclohexylalanine, 2-amino-4-cyclohexylbutyricacid His: histidine HOBT: hydroxylbenzotriazol HOSucc:hydroxysuccinimide HPLC: high-performance liquid chromatography Hyp:hydroxyproline Ind-2-COOH: indoline-2-carboxylic acid iPr: isopropylLeu: leucine Lsg: solution Lys: lysine m: multiplet Me: methyl MPLC:medium-performance liquid chromatography MTBE: methyl-tert-butyl etherNBS: N-bromosuccinimide Nva: norvaline Ohi-2-COOH:octahydroindole-2-carboxylic acid Ohii-1-COOH:octahydro-isoindole-1-carboxylic acid Orn: ornithine Oxaz: oxazolep-amb: p-amidinobenzyl Ph: phenyl Phe: phenylalanine Phg: phenylglycinePic: pipecolic acid pico: picolyl PPA: propylphosphonic anhydride Pro:proline Py: pyridine Pyr: 3,4-dehydroproline q: quartet RP-18: reversedphase C 18 RT: room temperature s: singlet Sar: sarcosine(N-methylglycine) sb: singlet broad t: triplet t: tertiary (tert) tBu:tert-butyl tert: tertiary (tert) TBAB: tetrabutylammonium bromide TEA:triethylamine TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydridethiaz: thiazole Thz-2-COOH: 1,3-thiazolidine-2-carboxylic acidThz-4-COOH: 1,3-thiazolidine-4-carboxylic acid thioph: thiophene 1-Tic:1-tetrahydro-isoquinoline carboxylic acid 3-Tic:3-tetrahydro-isoquinoline carboxylic acid TOTU:O-(cyanoethoxycarbonylmethylene)amino-1-N,N,N′,N′- tetramethyluroniumtetra-fluoroboronate(?) Z: carbobenzoxy

[0466] Experimental Section

[0467] The compounds of formula I can be represented by schemes I andII.

[0468] The building blocks A—B, D, E, G and K are preferably madeseparately and used in a suitably protected form (cf scheme I, whichillustrates the use of orthogonal protective groups (P or P*) compatiblewith the synthesis method used.

[0469] Scheme I describes the linear structure of the molecule Iachieved by elimination of protective groups from P—K—L* (L* denotesCONH₂, CSNH₂, CN, C(═NH)NH—COOR*; R* denotes a protective group orpolymeric carrier with spacer (solid phase synthesis)), coupling of theamine H—K—L* to the N-protected amino acid P—G—OH to form P—G—K—L*,cleavage of the N-terminal protective group to form H—G—K—L*, couplingto the N-protected amino acid P—E—OH to produce P—EG—K—L*, re-cleavageof the N-terminal protective group to form H—E—G—K—L* and optionallyrecoupling to the N-protected building block P—D—U (U=leaving group) toform P—D—E—G—K—L*, if the end product exhibits a building block D.

[0470] If L* is an amide, thioamide or nitrile function at thissynthesis stage, it will be converted to the corresponding amidine orhydroxyamidine function, depending on the end product desired. Amidinesyntheses for the benzamidine, picolylamidine, thienylamidine,furylamidine, and thiazolylamidine compounds of the structure type Istarting from the corresponding carboxylic acid amides, nitriles,carboxythioamides, and hydroxyamidines have been described in a numberof patent applications (cf, for example, WO 95/35309, WO 96/178860, WO96/24609, WO 96/25426, WO 98/06741, and WO 98/09950.

[0471] After splitting-off the protective group P to form H—(D)—E—G—K—L*(L* denotes C(═NH)NH, C(═NOH)NH, or (═NH)NH—COOR*; R* denotes aprotective group or a polymeric carrier with spacer (solid-phasesynthesis), coupling is effected to the optionally protected (P)—A—B—Ubuilding block (U=leaving group) or by hydroalkylation with (P)—A—B′—U(U=aldehyde, ketone) to produce (P)—A—B—(D)—E—G—K—L*.

[0472] Any protective groups still present are then eliminated. If L*denotes a C(═NH)NH spacer polymer support, these compounds areeliminated from the polymeric support in the final stage, and the activesubstance is thus liberated.

[0473] Scheme II describes an alternative route for the preparation ofthe compounds I by convergent synthesis. The appropriately protectedbuilding blocks P—D—E—OH and H—G—K—L* are linked to each other, theresulting intermediate product P—D—E—G—K—L* is converted to P—D—E—G—K—L*(L* denotes C(═NH)NH, C(═NOH)NH, or (═NH)NH—COOR*; R* denotes aprotective group or a polymeric support with spacer (solid-phasesynthesis), the N-terminal protective group is eliminated, and theresulting product H—D—E—G—K—L* is converted to the end product accordingto scheme I.

[0474] The N-terminal protective groups used are Boc, Cbz, or Fmoc, andC-terminal protective groups are methyl, tert-butyl and benzyl esters.Amidine protective groups for the solid-phase synthesis are preferablyBoc, Cbz, and derived groups. If the intermediate products containolefinic double bonds, then protective groups that are eliminated byhydrogenolysis are unsuitable.

[0475] The necessary coupling reactions and the conventional reactionsfor the provision and removal of protective groups are carried out understandardized conditions used in peptide chemistry (cf M. Bodanszky, A.Bodanszky, “The Practice of Peptide Synthesis”, 2nd Edition, SpringerVerlag Heidelberg, 1994).

[0476] Boc protective groups are eliminated by means of dioxane/HCl orTFA/DCM, Cbz protective groups by hydrogenolysis or with HF, and Fmocprotective groups with piperidine. Saponification of ester functions iscarried out with LiOH in an alcoholic solvent or in dioxane/water.tert-Butyl esters are cleaved with TFA or dioxane/HCl.

[0477] The reactions were monitored by DC, in which the following mobilesolvents were usually employed: A. DCM/MeOH 95:5 B. DCM/MeOH  9:1 C.DCM/MeOH  8:2 D. DCM/MeOH/HOAc 50% 40:10:5 E. DCM/MeOH/HOAc 50% 35:15:5

[0478] If column separations are mentioned, these separations werecarried out over silica gel, for which the aforementioned mobilesolvents were used.

[0479] Reversed phase HPLC separations were carried out withacetonitrile/water and HOAc buffer.

[0480] The starting compounds can be produced by the following methods:

[0481] Building Blocks A—B:

[0482] The compounds used as building blocks A—B are for the most partcommercially available sugar derivatives. If these compounds haveseveral functional groups, protective groups are introduced at therequired sites. If desired, functional groups are converted to reactivegroups or leaving groups (eg, carboxylic acids to active esters, mixedanhydrides, etc.), in order to make it possible to effect appropriatechemical linking to the other building blocks. The aldehyde or ketofunction of sugar derivatives can be directly used for hydroalkylationwith the terminal nitrogen of building block D or E.

[0483] The Synthesis of Building Blocks D is Carried Out as Follows:

[0484] The building blocks D—4-aminocyclohexanoic acid, 4-aminobenzoicacid, 4-aninomethylbenzoic acid, 4-aminomethylphenylacetic acid, and4-aminophenylacetic acid—are commercially available.

[0485] The Synthesis of the Building Blocks E Was Carried Out asFollows:

[0486] The compounds used as building locks E-glycine, (D)- or(L)-alanine, (D)- or (L)-valine, (D)-phenylalanine,(D)-cyclohexylalanine, (D)-cycloheptylglycine, D-diphenylalanine, etc.are commercially available as free amino acids or as Boc-protectedcompounds or as the corresponding methyl esters.

[0487] Preparation of cycloheptylglycine and cyclopentylglycine wascarried out by reaction of cycloheptanone or cyclopentanone respectivelywith ethyl isocyanide acetate according to known instructions (H. -J.Prätorius, J. Flossdorf, M. Kula, Chem. Ber. 1985, 108, 3079, or U.Schöllkopf and R. Meyer, Liebigs Ann. Chem. 1977, 1174). Preparation of(D)-dicyclohexylalanine was carried out by hydrogenation after T. J.Tucker et al, J. Med. Chem. 1997, 40., 3687-3693.

[0488] The said amino acids were provided by well-known methods with anN-terminal or C-terminal protective group depending on requirements.

[0489] Synthesis of the Building Blocks G Was Carried Out as Follows:

[0490] The compounds used as building blocks G—(L)-proline,(L)-pipecolinic acid, (L)-4,4-difluoroproline, (L)-3-methylproline,(L)-5-methylproline, (L)-3,4-dehydroproline,(L)-octahydroindole-2-carboxylic acid, (L)-thiazolidine-4-carboxylicacid, and (L)-azetidine carboxylic acid—are commercially available asfree amino acids or as Boc-protected compounds or as correspondingmethyl esters.

[0491] (L)-Methyl thiazolidine-2-carboxylate was prepared after R. L.Johnson, E. E. Smissman, J. Med.Chem. 21, 165 (1978).

[0492] Synthesis of the Building Blocks K Was Carried Out as Follows:

[0493] p-Cyanobenzylamine

[0494] Preparation of this building block was carried out as describedin WO 95/35309.

[0495] 3-(6-Cyano)picolylamine

[0496] Preparation of this building block was carried out as describedin WO 96/25426 or WO 96/24609.

[0497] 5-Aminomethyl-2-cyanothiophen

[0498] Preparation of this building block was carried out as describedin WO 95/23609.

[0499] 5-Aminomethyl-3-cyanothiophen

[0500] Preparation of this building block was carried out starting from2-formyl-4-cyanothiophen in a manner similar to that described for2-formyl-5-cyanothiophen (WO 95/23609).

[0501] 2-Aminomethylthiazole-4-thiocarboxamide

[0502] Preparation was carried out according to G. Videnov, D. Kaier, C.Kempter and G. Jung, Angew. Chemie (1996) 108, 1604, where theN-Boc-protected compound described in said reference was deprotectedwith ethereal hydrochloric acid in dichloromethane.

[0503] 5-Aminomethy-2-cyanofuran

[0504] Preparation of this building block was carried out as describedin WO 96/17860.

[0505] 5-Aminomethyl-3-cyanofuran

[0506] Preparation of this building block was carried out as describedin WO 96/17860.

[0507] 5-Aminomethyl-3-methylthiophene-2-carbonitrile

[0508] Preparation of this building block was carried out as describedin WO 99/37668.

[0509] 5-Aminomethyl-3-chlorothiophene-2-carbonitrile

[0510] Preparation of this building block was carried out as describedin WO 99/37668.

[0511] 5-Aminomethyl-4-methylthiophene-3-thiocarboxamide

[0512] Preparation of this building block was carried out as describedin WO 99/37668.

[0513] 5-Aminomethyl-4-chlorothiophene-3-thiocarboxamide

[0514] Preparation of this building block was carried out as describedin WO 99/37668.

[0515] 2-Aminomethyl-4-cyanothiazole:

[0516] a) Boc-2-aminomethylthiazole-4-carboxamide

[0517] To a solution of Boc-glycinethioamide (370 g, 1.94 mol) in 3.9liters of ethanol there was added ethyl bromopyruvate (386 g, 1.98 mol)dropwise at 10° C., and the mixture was stirred over a period of 5 h atfrom 20° to 25° C. Then 299 mL of 25% strength aqueous ammonia wereadded.

[0518] 940 mL of this mixture (equivalent to 19.9% of the total volume)were taken and 380 mL of ethanol were removed therefrom by distillation,after which 908 mL of 25% strength aqueous ammonia were added, and themixture was stirred for 110 h at from 20° to 25° C. The mixture wascooled to 0° C., and the solids were filtered off and washed twice withwater and dried. There were obtained 60.1 g of Boc-protected thiazolecarboxamide having an HPLC purity of 97.9 areal %, corresponding to ayield for these two stages of 60.5%.

[0519]¹H-NMR (DMSO-d6, in ppm): 8.16 (s, 1H, Ar—H), 7.86 (t, broad, 1H,NH), 7.71 and 7.59 (2x s, broad, each 1H, NH₂), 4.42 (d, 2H, CH₂), 1.41(s, 9H, tert-butyl).

[0520] b) 2-Aminomethyl-4-cyanothiazole hydrochloride

[0521] Boc-2-aminomethylthiazole 4-carboxamide (75.0 g, 0.29 mol) wassuspended in 524 mL of dichloromethane and triethylamine (78.9 g, 0.78mol) and 79.5 g (0.38 mol) of trifluoroacetic anhydride were addedthereto at from −5° to 0° C. Stirring was continued over a period of 1h, the mixture heated to from 20° to 25° C. and 1190 mL of water added,and the phases were separated. To the organic phase there were added 160mL of from 5 to 6N isopropanolic hydrochloric acid, and the mixture washeated at boiling temperature over a period of 3 h and then at from 20°to 25° C. overnight with stirring, after which it was cooled to from −5°to 0° C. for 2.5 h prior to removal of the solids by filtering. Thissolid material was washed with dichloromethane and dried. There wereobtained 48.1 g of 2-aminomethylcyanothiazole having an HPLC purity of99.4 areal %, which is equivalent to a yield for these two stages of94.3%.

[0522]¹H-NMR (DMSO-d6, in ppm): 8.98 (s, broad, 2H, NH₂), 8.95 (s, 1 h,Ar—H), 4.50 (s, 2H, CH₂).

[0523] 5-Aminomethyl-3-amidinothiophene bishydrochloride

[0524] Synthesis of this compound was carried out starting from5-aminomethyl-3-cyanothiophene by reaction with (Boc)₂O to form5-tert-butyl-oxycarbonylaminomethyl-3-cyanothiophene, conversion of thenitrile function to the corresponding thioamide by the addition ofhydrogen sulfide, methylation of the thioamide function withiodomethane, reaction with ammonium acetate to produce the correspondingamidine followed by protective group elimination with hydrochloric acidin isopropanol to give 5-aminomethyl-3-amidinothiophenebishydrochloride.

[0525] Building Blocks for Solid-Phase Synthesis:

[0526]3-Amidino-5-[N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]aminomethylthiophenehydrochloride

[0527] 3-Amidino-5-aminomethylthiophene bishydrochloride (1.3 g, 5.7mmol) was placed in DMF (15 mL), and N,N-diisopropylethylamine (0.884 g,6.84 mmol) was added. Following stirring for 5 min at room temperaturethere were added acetyldimedone (1.25 g, 6.84 mmol) andtrimethoxymethane (3.02 g, 28.49 mmol). Stirring was continued for 2.5 hat room temperature, after which the DMF was removed in high vacuum andthe residue was stirred with DCM (5 mL) and petroleum ether (20 mL). Thesolvent was decanted from the pale yellow product and the solid matterwas dried in vacuo at 40° C. Yield: 1.84 g (5.2 mmol, 91%).

[0528]¹H-NMR (400 MHz, [D6]DMSO, 25° C., TMS): delta=0.97 (s, 6H); 2.30(s, 4H); 2.60 (s, 4H); 4.96 (d, J=7 Hz, 2H); 7.63 (s, 1H); 8.60 (s, 1H);9.07 (sbr, 2H); 9.37 (sbr, 1H.

[0529] Syntheses of Building Blocks H—G—K—CN:

[0530] The synthesis of the H—G—K—CN building block is exemplarilydescribed in WO 95/35309 for prolyl-4-cyanobenzylamide, in WO 98/06740for 3,4-dehydroprolyl-4-cyanobenzylamide and in WO 98/06741 for3,4-dehydroprolyl-5-(2-cyano)thienylmethylamide. The preparation of3,4-dehydroprolyl-5-(3-cyano)thienylmethylamide is similarly carried outby coupling Boc-3,4-dehydroproline to 5-aminomethyl-3-cyanothiophenhydrochloride followed by protective group elimination.

[0531] The synthesis of 3,4-dehydroprolyl-[2(4-cyano)thiazolmethyl]amidehydrochloride was carried out by coupling Boc-3,4-dehydroproline to2-aminomethyl-4-cyanothiazole hydrochloride followed by protective groupelimination.

[0532] H—E—G—K—C(═NOH)NH₂:

[0533] The synthesis of the building block H—E—G—K—C(═NOH)NH₂ isexemplarily described for H—(D)-Cha-Pyr-NH—CH₂-2-(4-ham)thiaz

[0534] a)(Boc)-(D)-cyclohexylalanyl-3,4-dehydroprolyl-[2-(4-cyano)thiazolyl]methylamide

[0535] (Boc)-(D)-Cha-OH (21.3 g, 271.4 mmol) andH-Pyr-NH—CH₂-2(4-CN)-thiaz hydrochloride (21.3 g, 270.7 mmol) weresuspended in dichloromethane (750 mL) and to the suspension there wasadded ethyldiisopropylamine (50.84 g, 67.3 mL, 393.4 mmol), which gave aclear, slightly reddish solution. The reaction mixture was cooled to ca10° C., and a 50% strength solution of propylphosphonic anhydride inethyl acetate (78.6 mL, 102.3 mmol) was added dropwise. Followingstirring overnight at RT, the mixture was concentrated in vacuo, theresidue taken up in water and the mixture stirred for 30 min to effecthydrolysis of the excess propylphosphonic anhydride. The acid solutionwas then extracted 3 times with ethyl acetate and once withdichloromethane, the organic phases being washed with water, dried, andevaporated in vacuo in a rotary evaporator. The two residues werecombined, dissolved in dichloromethane and precipitated with n-pentane.This procedure was repeated and 33.4 g of(Boc)-(D)-Cha-Pyr-NH—CH₂-2(4CN)thiaz (yield 87%) were obtained as whitesolid.

[0536] b)(Boc)-(D)yclohexylalanyl-3,4-dehydroprolyl-[2-(4-hydroxamidino)thiazolyl]methylamide

[0537] (Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (26.3 g, 53.9 mmol) wasdissolved in methanol (390 mL), to the solution there was addedhydroxylamine hydrochloride (9.37 g, 134.8 mmol), and to this suspensiondiisopropylethylamine (69.7 g, 91.7 mL, 539.4 mmol) was slowly addeddropwise, with cooling (water bath). Following agitation at roomtemperature over a period of 3 h, the reaction solution was evaporatedin vacuo in a rotary evaporator, the residue taken up in ethylacetate/water, and the aqueous phase was set to pH 3 with 2Nhydrochloric acid and extracted 3 times with ethyl acetate and once withdichloromethane. The organic phases were washed a number of times withwater, dried over magnesium sulphate and evaporated in vacuo in a rotaryevaporator. The two residues were combined and stirred with n-pentane togive 26.8 g of (Boc)-(D)-Cha-Pyr-NH—CH₂-2(4-ham)-thiaz (yield 95%) as awhite solid.

[0538] c)(D)-cyclohexylalanyl-3,4-dehydroprolyl-[2-(-4-hydroxamidino)thiazolyl]methylamide

[0539] (Boc)-(D)-Cha-Pyr-NH—CH₂-2(4-ham)-thiaz (5.0 g, 9.6 mmol) wasdissolved in a mixture of isopropanol (50 mL) and dichloromethane (50mL) and to the solution there was added HCl in dioxane (4M solution, 24mL, 96 mmol) and stirring was continued for 3 h at room temperature. Asstarting material was still present, HCl in dioxane (4M solution, 12 mL,48 mmol) was again added and the mixture stirred at room temperatureovernight. The reaction mixture was evaporated in vacuo in a rotaryevaporator, and co-distilled a number of times with ether anddichloromethane to remove adhering hydrochloric acid. The residue wasdissolved in a little methanol and precipitated with a large quantity ofether. There were obtained 4.3 g of H—(D)-Cha-Pyr-NH—CH₂-2(4-ham)thiazhydrochloride (yield 98%).

[0540] H—E—G—K—C(═NH)NH₂:

[0541] The synthesis of the H—E—G—K—C(═NH)NH₂ building block isexemplarily described for H—(D)-Cha-Pyr-NH—CH₂-2(4-am)thiaz.

[0542] a)(Boc)-(D)-cyclohexylalanyl-3,4-dehydroprolyl-[2-(4-amidino)thiazolyl]methylamide

[0543] (Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (27.0 g, 55.4 mmol) andN-acetyl-L-cysteine (9.9 g, 60.9 mmol) were dissolved in methanol (270mL), heated under reflux, while ammonia was introduced over a period of8 h. Since the reaction was still non-quantitative after DC checking,N-acetyl-L-cysteine (2.0 g, 12.0 mmol) was again added and the mixtureheated under reflux for a further 8 h with introduction of ammonia. Thereaction mixture was then concentrated in vacuo, and the residue wassuccessively stirred in ether and dichloromethane/ether 9:1. Theresulting crude product (Boc)-(D)-Cha-Pyr-NH—CH₂-2(4-am)thiaz, whichstill contained N-acetyl-L-cysteine, was used without furtherpurification in the next stage.

[0544] b)(D)-cyclohexylalanyl-3,4-dehydroprolyl-[2(4-amidino)thiazolyl]methylamide

[0545] (Boc)-(D)-Cha-Pyr-NH—CH₂-2(4-am)thiaz (crude product, see above)was dissolved in a mixture of methanol (20 mL) and dichloromethane (400mL), and to the solution there was added HCl in dioxane (4M solution,205 mL, 822 mmol) and stirring was continued overnight at roomtemperature.

[0546] As starting material was still present, HCl in dioxane was againadded and stiring carried out overnight at room temperature. Thereaction mixture was evaporated in vacuo in a rotary evaporator, andco-distilled a number of times with ether and dichloromethane to removeadhering hydrochloric acid. The residue was taken up in water andextracted 20 times with dichloromethane to remove N-acetyl-L-cysteine,and the aqueous phase was then lyophilized. The lyophilized matter wasstirred out from ether to give 31.8 g ofH(D)-Cha-Pyr-NH—CH₂-2(4-am)thiaz dihydrochloride (yield over 2 stages:81%).

[0547] The preparation of the building blockH—E—G—K—C(═NH)NH₂H—(D)-Chg-Aze-NH 4-amb is described in WO 94/29336Example 55. H—(D)-Chg-Pyr-NH—CH₂5-(3-am)-thioph was synthesized in asimilar manner to that used for H—(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz, theformation of amidine being effected using the corresponding nitrileprecursor Boc-(D)-Chg-Pyr-NH—CH₂-5-(3-CN)-thioph as described in WO9806741 Example 1 via intermediate stagesBoc-(D)-Chg-Pyr-NH—CH₂-5-(3CSNH₂)-thioph andBoc-(D)-Chg-Pyr-NH—CH₂-5-(3-C(═NH)S—CH₃)-thioph.

EXAMPLE 1

[0548] (D)-Arabino-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz xCH₃COOH

[0549] H—(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz dihydrochloride (2.0 g, 4.19mmol) was dissolved in methanol (30 mL), and to the solution there wereadded D-(−)-arabinose (0.63 g, 4.19 mmol) and molecular sieve (4Angstrom). The mixture was stirred over a period of 1 h at roomtemperature and sodium cyanoborohydride was then added portion wise,during which operation slight generation of gas occurred. Followingstirring overnight at room temperature, the molecular sieve was filteredoff in vacuo, the filtrate concentrated in vacuo and the residue stirredin acetone. The crude product filtered off in vacuo was purified bymeans of MPLC (RP-18 column, acetonitrile/watter/glacial acetic acid)and then lyophilized to give 840 mg of(D)-Arabino-(D)-Cha-Pyr-NH—CH₂-2-(4-am)thiaz xCH₂COOH as a white solid(yield 34%).

[0550] ESI-MS: M+H⁺: 539.

EXAMPLE 2

[0551] (L)-Arabino-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz xCH₃COOH

[0552] This compound was synthesized in a manner similar to thatdescribed in Example 1 but starting from L-(+)-arabinose.

[0553] ESI-MS: M+H⁺: 539.

EXAMPLE 3

[0554] (D)-Erythro-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-diaz xCH₃COOH

[0555] This compound was synthesized-in a manner similar to thatdescribed in Example 1 but starting from D-(+)-erythrose.

[0556] ESI-MS: M+H⁺: 509.

EXAMPLE 4

[0557] (L)-Erythro-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz xCH₃COOH

[0558] This compound was synthesized in a manner similar to thatdescribed in Example 1 but starting from L-(+)-erythrose.

[0559] ESI-MS: M+H⁺: 509.

EXAMPLE 5

[0560] (D)-Glycer-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz xCH₃COOH

[0561] This compound was synthesized in a manner similar to thatdescribed in Example 1 but starting from D-(+)-glycerinaldehyde.

[0562] ESI-MS: M+H⁺: 479.

EXAMPLE 6

[0563] (L)-Glycer-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz xCI₃COOH

[0564] This compound was synthesized in a manner similar to thatdescribed in Example 1 but starting from L-(+)-glycerinaldehyde.

[0565] ESI-MS: M+H⁺: 479.

EXAMPLE 7

[0566] (L)-Rhamno-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz xHCl

[0567] This compound was synthesized in a manner similar to thatdescribed in Example 1 but starting from L-rhamnose.

[0568] L-rhamnnose (0.82 g, 5 mmol) was dissolved in water (20 mL) atroom temperature and H—(D)-Cha-Pyr-NH—CH₂-2(4-am)thiaz dihydrochloride(2.4 g, 5 mmol) was stirred in. The clear solution became viscous after20 min. Sodium cyanoborohydride was added portion wise in an equimolaramount over a period of 4 h to give a white precipitate, which dissolvedon the addition of ethanol (2 mL). 5 mL of 1M HCl set the pH to 3 andsolid was precipitated 3 times with 300 mL of acetone each time. Thesolid was removed by centrifugation and dissolved in water (100 mL).Following lyophilization there were obtained 2.6 g of(L)Rhamno-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz xHCl as a white powder.

EXAMPLE 8

[0569] (D)-Melibio-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz xHCl

[0570] This compound was synthesized in a manner similar to thatdescribed in Example 7 but starting from D-melibiose.

[0571] D-melibiose (1.8 g, 5 mmol) was dissolved in water (20 mL) atroom temperature and H—(D)-Cha-Pyr-NH—CH₂-2-(4-am)thiaz dihydrochloride(2.4 g, 5 mmol) was stirred in. The clear pale yellow solution becameviscous after 20 min. An equimolar amount of sodium cyanoborohydride wasadded portion wise over a period of 4 h. There was obtained a whitesolid precipitate, to which 2 mL of ethanol were added to give a clearsolution. The pH was set to pH 5 with 5 mL of 1M HCl and precipitationwas effected 3 times with 300 mL of acetone each time. Followingcentrifugation, the sediment obtained was taken up in 100 mL of waterand the solution lyophilized.

[0572] Yield: 3,2 g of (D)-Melibio-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiazxHCl.

EXAMPLE 9

[0573] (D)-Gluco-(D)-Chg-Pyr-NH—CH₂-5-(3-am)-thioph xHCl

[0574] This compound was synthesized in a manner similar to thatdescribed in Example 7 but starting from D-glucose.

[0575] D-glucose (1.0 g, 5.6 mmol) was dissolved in 20 mL of water atroom temperature and H—(D)-Chg-Pyr-NH—CH₂-5-(3-am)thioph dihydrochloride(3.0 g, 6.5 mmol) was stirred in. The clear solution became viscousafter 10 min. An equimolar amount of sodium cyanoborohydride was addedportion wise over a period of 4 h to give a white precipitate. Aftercooling in an ice bath with 3×5 mL of H2O the mixture were shaken andthe sediment was taken up in 20 mL of H₂O and the pH set to pH 5.0 withca 5 mL of 0.1 M NaOH. 1st precipitation using 300 mL of acetone. 2ndprecipitation: the sediment was taken up in 30 mL of H₂O and 300 mL ofacetone were added. The sediment was dissolved in H₂O and neutralizedwith 2 mL of 1M HCl; the solution was then lyophilized. Yield: 1,52 g(D)-Gluco-(D)-Chg-Pyr-NH—CH₂-5-(3-am)-thioph xHCl als weiβes Pulver.

EXAMPLE 10

[0576] Maltohexao-(D)-Chg-Pyr-NH—CH₂-5-(3-am)-thioph xHCl

[0577] This compound was synthesized in a manner similar to thatdescribed in Example 7 but starting from maltohexaose.

[0578] Maltohexaose (2 g, 2 mmol) was dissolved in water (20 mL) at roomtemperature and H—(D)-Chg-Pyr-NH—CH₂-5-(3-am)thioph dihydrochloride(0.92 g, 2 mmol) was stirred in. The clear solution became viscous after10 min; an equimolar amount of sodium cyanoborohydride was added portionwise over a period of 4 h; after cooling in an ice bath, precipitationwas effected with 8 volumes of ethanol. The sediment was reprecipitatedwith 300 mL of ethanol. The sediment was dissolved in water and thesolution lyophilized.

EXAMPLE 11

[0579] (D)-Cellobio-(D)-Chg-Pyr-NH—CH₂-5-(3-am)-thioph xHCl

[0580] This compound was synthesized in a manner similar to thatdescribed in Example 7 but starting from cellobiose.

[0581] Cellobiose (2 g, 6 mmol) was stirred into water (20 mL) at 50° C.and H—(D)-Chg-Pyr-NH—CH₂-5(3-am)thioph dihydrochloride (2.8 g, 6 mmol)added. The turbid solution became viscous as an equimolar amount ofsodium cyanoborohydride was added portion wise over a period of 4 h.Stirring was continued for approximately one hour at 50° C.Approximately 10 mL of 1 M HCl were aded to set the pH to 3.Precipitation was then effected twice with 300 mL of acetone. Followingcooling in an ice bath, the sediment was taken up in 60 mL of water andreprecipitated with 600 mL of acetone. The sediment was dissolved inwater and the solution lyophilized. Yield: 4,4 g(D)-Cello-bio-(D)-Chg-Pyr-NE—CH₂-5(3-am)-thioph xHCl.

EXAMPLE 12

[0582] (D)-Glucuronic-(D)-Chg-Pyr-NH—CH₂-5-(3-am)-thioph

[0583] This compound was synthesized in a manner similar to thatdescribed in Example 7 but starting from the sodium salt of D-glucuronicacid.

[0584] The sodium salt of D-glucuronic acid xH2O (1.4 g, 6 mmol) wasdissolved in water (20 mL) at room temperature andH—(D)-Chg-Pyr-NH—CH₂-5-(3-am)thioph dihydrochloride (2.8 g, 6 mmol) wasstirred in at room temperature. The clear solution turned pale yellowafter 10 min. An equimolar amount of 330 mg of sodium cyanoborohydridewas added portion wise over a period of 4 h to give a solid, compactprecipitate. 4 mL of 0.1 M NaOH were added and the supernatant wasdecanted off and the precipitate stirred up in acetone. The sediment wastaken up in 40 mL of H₂O and 3 mL of 1M HCl were added to give a pH of4. The compound passed into solution. Precipitation was effected with400 mL of acetone. The sediment was then dissolved in water and thesolution lyophilized. Yield: 3,1 g(D)-Glucuronic-(D)-Chg-Pyr-NH—CH₂-5(3-am)-thioph.

EXAMPLE 13

[0585] (D)-Gluco-(D)-Chg-Aze-NH-4-amb xHCl

[0586] This compound was synthesized in a manner similar to thatdescribed in Example 7 but starting from D-glucose.

[0587] D-glucose (2.5 g, 14 mmol) was dissolved in water (40 mL) at roomtemperature and H—(D)-Chg-Aze-NH-4-amb (WO 94/29336 Example 55; 6.8 g;15.4 mmol) was stirred in. An equimolar amount of sodiumcyanoborohydride was added portion wise over a period of 4 h and themixture was then stirred overnight. There was obtained a greasy, viscousemulsion. 50 mL of water were added, after which ethanol was added untilthe solution became clear.

[0588] The pH was adjusted to 4.0 with ca 15 mL of 0.1M HCl. 1stprecipitation using 600 mL of acetone. 2nd precipitation: the sedimentwas taken up in 50 mL of water and 600 mL of acetone were added; thesediment was redissolved in water and the solution lyophilized. Yield:7,8 g (D)-Gluco-(D)-Chg-Aze-NH4-amb xHCl.

EXAMPLE 14

[0589] Malto-(D)-Chg-Aze-NH-4-amb xHCl

[0590] This compound was synthesized in a manner similar to thatdescribed in Example 7 but starting from maltose.

[0591] Maltose xH₂O (5 g, 14 mmol) was dissolved in 40 mL of water atroom temperature and H-Chg-Aze-NH-4-amb (6.8 g; 15.4 mmol) was stirredin. There followed a portion wise addition of an equimolar amount ofsodium cyanoborohydride over a period of 4 h. The initially clear,viscous solution slowly changed to a greasy, viscous emulsion. 50 mL ofwater were added followed by ca 15 mL 0.1 M HCl to give a pH of 4.0. 1stprecipitation using 600 mL of acetone. 2nd precipitation: the sedimentwas taken up in 50 mL of water and 600 mL of acetone were added; thesediment was redissolved in water and the solution lyophilized. Yield:10,1 g Malto-(D)-Chg-Aze-NH-4-amb xHCl.

EXAMPLE 15

[0592] (L)-Erythro-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz xCH₃COOH

[0593] This compound was synthesized in a manner similar to thatdescribed in Example 1 but starting from L-(+)-erythrose andH—(D)-Cha-Pyr-NH—CH₂-2-(4-ham)thiaz.

[0594] ESI-MS: M+H⁺: 525.

EXAMPLE 16

[0595] (L)-Arabino-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz xCH₃COOH

[0596] This compound was synthesized in a manner similar to thatdescribed in Example 1 but starting from L-(+)-arabinose andH—(D)-Cha-Pyr-NH—CH₂-2-(4-ham)thiaz.

[0597] ESI-MS: M+H⁺: 555.

Example 17

[0598] Malto-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz

[0599] This compound was synthesized in a manner similar to thatdescribed in Example 1 but starting from maltose.

[0600] H—(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz Maltose xH2O(2.2 g, 6 mmol)was dissolved in 40 mL of water and 60 mL of ethanol at room temperatureand H—(D)-Cha-Pyr-NH—CH₂-2-(4ham)-thiaz (2.8 g, 6.6 mmol) was stirredin. The portion wise addition of an equimolar amount of sodiumcyanoborohydride over a period of 8 h gave a highly viscous, clear,brownish solution. 1st precipitation using 500 mL of acetone. Thesediment was dissolved in 50 mL of water and set to pH 7.5 with 0.1 M ofHCl followed by precipitation with 500 mL of acetone. The sediment wasdissolved in 100 mL of water and the solution lyophilized. Yield: 3,6 gMalto-(D)-Cha-Pyr-NH—CH₂-4-ham)thiaz.

[0601] For the following compounds, the thrombin time was determinedaccording to Example A: Example No. Thrombin time EC₁₀₀ [mol/L] 10 2.4E−08 12  1.4E−08 9  1.5E−08 11  2.1E−08 14  2.1E−08 13  2.1E−08 81.64E−08 7 9.68E−09 2  1.4E−08

1. A compound of the general formula (I) A—B—D—E—G—K—L  (I), in which Astands for H, CH₃, H—(R^(A1))i^(A) in which R^(A1) denotes

 in which R^(A2) denotes H, NH₂, NH—COCH₃, F, or NHCHO, R^(A3) denotesH, or CH₂OH, R^(A4) denotes H, CH₃, or COOH, _(i)A is 1 to 20, _(j)A is0, 1, or 2, _(k)A is 2 or 3, _(l)A is 0 or 1, _(m)A is 0, 1, or 2, _(n)Ais 0, 1, or 2, the groups R^(A1) being the same or different when _(i)Ais greater than 1, B denotes

A—B stands for

 or for a neuraminic acid radical or N-acetylneuraminic acid radicalbonded through the carboxyl function,  in which R^(B1) denotes H, CH₂OH,or C₁₋₄ alkyl, R^(B2) denotes H, NH₂, NH—COCH₃, F, or NHCHO, R^(B3)denotes H, C₁₋₄ alkyl, CH₂—O—(C₁₋₄ alkyl), COOH, F, NH—COCH₃, or CONH₂,R^(B4) denotes H, C₁₋₄ alkyl, CH₂—O—(C₁₋₄ alkyl), COOH, or CHO, in whichlatter case intramolecular acetal formation may take place, R^(B5)denotes H, C₁₋₄ alkyl, CH₂—O—(C₁₋₄ alkyl), or COOH, _(k)B is 0 or 1,_(l)B is 0, 1, 2, or 3 (_(l)B≠0 when A=R B=R^(B3)=H, _(m)B=_(k)B=0 and Dis a bond), _(m)B is 0, 1, 2, 3, or 4, _(n)B is 0, 1, 2, or 3, R^(B6)denotes C₁₋₄ alkyl, phenyl, or benzyl, and R^(B7) denotes H, C₁₋₄ alkyl,phenyl, or benzyl, D stands for a bond or for

 in which R^(D1) denotes H or C₁₋₄ alkyl, R^(D2) denotes a bond or C₁₋₄alkyl, R^(D3) denotes

 in which _(l)D is 1, 2, 3, 4, 5, or 6, R^(D5) denotes H, C₁₋₄ alkyl, orCl, and R^(D6) denotes H or CH₃, and in which a further aromatic oraliphatic ring can be condensed onto the ring systems defined forR^(D3), R^(D4) denotes a bond, C₁₋₄ alkyl, CO, SO₂, or —CH₂—CO, E standsfor

 in which _(k)E is 0, 1, or 2, _(l)E is 0, 1, or 2, _(m)E is 0, 1, 2, or3, _(n)E is 0, 1, or 2, _(p)E is 0, 1, or 2, R^(E1) denotes H, C₁₋₆alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, C₃₋₈ cycloalkyl having aphenyl ring condensed thereto, which groups may carry up to threeidentical or different substituents selected from the group consistingof C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, F, Cl, and Br, R^(E1) may also denoteR^(E4)OCO—CH₂— (where R^(E4) denotes H, C₁₋₁₂ alkyl, or C₁₋₃ alkylaryl),R^(E2) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl,indolyl, tetrahydropyranyl, tetrahydrothiopyranyl, diphenylmethyl,dicyclohexylmethyl, C₃₋₈ cycloalkyl having a phenyl ring condensedthereto, which groups may carry up to three identical or differentsubstituents selected from the group consisting of C₁₋₆ alkyl, OH,O—(C₁₋₆ alkyl), F, Cl, and Br, and may also denote CH(CH₃)OH orCH(CF₃)₂, R^(E3) denotes H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl,heteroaryl, C₃₋₈ cycloalkyl having a phenyl ring condensed thereto,which groups may carry up to three identical or different substituentsselected from the group consisting of C₁₋₆ alkyl, OH, O—(C₁₋₆ alkyl), F,Cl, and Br, the groups defined for R^(E1) and R^(E2) may beinterconnected through a bond, the groups defined for R^(E2) and R^(E3)may also be interconnected through a bond, R^(E2) may also denoteCOR^(E5) (where R^(E5) denotes OH, O—(C₁₋₆ alkyl), or O—(C₁₋₃alkylaryl)), CONR^(E6)R^(E7) (where R^(E6) and R^(E7) denote H, C₁₋₆alkyl, or C₀₋₃ alkylaryl), or NR^(E6)R^(E7), E may also stand for D-Asp,D-Glu, D-Lys, D-Orn, D-His, D-Dab, D-Dap, or D-Arg, G stands for

 where _(l)G is 2, 3, 4, or 5, and one of the CH₂ groups in the ring isreplaceable by O, S, NH, N(C₁₋₃ alkyl), CHOH, CHO(C₁₋₃ alkyl), C(C₁₋₃alkyl)₂, CH(C₁₋₃ alkyl), CHF, CHCl, or CF₂,

 in which _(m)G is 0, 1, or 2, _(n)G is 0, 1, or 2, _(p)G is 0, 1, 2, 3,or 4, R^(G1) denotes H, C₁₋₆ alkyl, or aryl, R^(G2) denotes H, C₁₋₆alkyl, or aryl, and R^(G1) and R^(G2) may together form a —CH═CH—CH═CH—chain, G may also stand for

 in which _(q)G is 0, 1, or 2, _(r)G is 0, 1, or 2, R^(G3) denotes H,C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or aryl, R^(G4) denotes H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, or aryl (particularly phenyl or naphthyl), K stands forNH—(CH₂)_(n)K—Q^(K)  in which _(n)K is 0, 1, 2, or 3, Q^(K) denotes C₂₋₆alkyl, whilst up to two CH₂ groups may be replaced by O or S, Q^(K) alsodenotes

 in which R^(K1) denotes H, C₁₋₃ alkyl, OH, O—C(₁₋₃ alkyl), F, Cl, orBr, R^(K2) denotes H, C₁₋₃ alkyl, O—(C₁₋₃ alkyl), F, Cl, or Br, X^(K)denotes O, S, NH, N—(C₁₋₆ alkyl), Y^(K) denotes

Z^(K) denotes

U^(K) denotes

V^(K) denotes

W^(K) denotes

 but in the latter case L may not be a guanidine group, _(n)K is 0, 1,or 2, _(p)K is 0, 1, or 2, _(q)K is 1 or 2, L stands for

 in which R^(L1) denotes H, OH, O—(C₁₋₆ alkyl), O—(CH₂)₀₋₃-phenyl,CO—(C₁₋₆ alkyl), CO₂—(C₁₋₄ alkyl), or CO₂—(C₁₋₃ alkylaryl), and thetautomers thereof, stereoisomers thereof, salts thereof withpharmacologically acceptable acids or bases, and the prodrugs thereof.2. A compound of the general formula (I) A—B—D—E—G—K—L  (I), in which Astands for H or H—(R^(A1))i^(A) in which R^(A1) denotes

 in which R^(A4) denotes H, CH₃, or COOH, _(i)A is 1 to 6, _(j)A is 0,1, or 2, _(k)A is 2 or 3, _(m)A is 0, 1, or 2, _(n)A is 0, 1, or 2, thegroups R^(A1) being the same or different when _(i)A is greater than 1;B denotes

A—B stands for

 in which R^(B1) denotes H or CH₂OH, R^(B2) denotes H, NH₂, NH—COCH₃, orF, R^(B3) denotes H, CH₃, CH₂—O—(C₁₋₄ alkyl), or COOH, R^(B4) denotes H,C₁₋₄ alkyl, CH₂—O—(C₁₋₄ alkyl), COOH, or CHO, in which latter caseintramolecular acetal formation may take place, R^(B5) denotes H, CH₃,CH₂—O—(C₁₋₄ alkyl), or COOH, _(k)B is 0 or 1, _(l)B is 0, 1, 2, or 3(_(l)B≠0 when A=R^(B1)=R^(B3)=H, _(m)B=_(k)B=0, and D is a bond), _(m)Bis 0, 1, 2, or 3, _(n)B is 0, 1, 2, or 3, R^(B6) denotes C₁₋₄ alkyl,phenyl, or benzyl, and R^(B7) denotes H, C₁₋₄ alkyl, phenyl, or benzyl,D stands for a bond or for

 in which R^(D1) denotes H or C₁₋₄ alkyl, R^(D2) denotes a bond or C₁₋₄alkyl, R^(D3) denotes

R^(D4) denotes a bond, C₁₋₄ alkyl, CO, SO₂, or —CH₂—CO, E stands for

 in which _(k)E is 0, 1, or 2, _(m)E is 0, 2, or 3, R^(E1) denotes H,C₁₋₆ alkyl, or C₃₋₈ cycloalkyl, which groups may carry up to threeidentical or different substituents selected from the group consistingof C₁₋₆ alkyl, OH, and O—C₁₋₆ alkyl, R^(E2) denotes H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl, heteroaryl, tetrahydropyranyl, diphenylmethyl, ordicyclohexylmethyl, which groups may carry up to three identical ordifferent substituents selected from the group consisting of C₁₋₆ alkyl,OH, O—(C₁₋₆ alkyl), F, Cl, and Br, and may also denote CH(CF₃)₂; R^(E3)denotes H, C₁₋₆ alkyl, or C₃₋₈ cycloalkyl, R^(E2) may also denoteCOR^(E5) (where R^(E5) denotes OH, O—C₁₋₆ alkyl, or O—(C₃ alkylaryl)),CONR^(E6)R^(E7) (where R^(E6) and R^(E7) denote H, C₁₋₆ alkyl, or C₀₋₃alkylaryl respectively), or NR^(E6)R^(E7); E may also stand for D-Asp,D-Glu, D-Lys, D-Orn, D-His, D-Dab, D-Dap, or D-Arg; G stands for

 where _(l)G is 2, 3, or 4, and one of the CH₂ groups in the ring isreplaceable by O, S, NH, N(C₁₋₃ alkyl), CHOH, or CHO(C₁₋₃ alkyl);

 in which _(m)G is 0, 1, or 2; _(n)G is 0, or 1; K stands forNH—(CH₂)_(n)K—Q^(K)  in which _(n)K is 1 or 2, Q^(K) denotes

 in which R^(K1) denotes H, C₁₋₃ alkyl, OH, O—(C₁₋₃ alkyl), F, Cl, orBr, R^(K2) denotes H, C₁₋₃ alkyl, O—(C₁₋₃ alkyl), F, Cl, or Br, X^(K)denotes O, S, NH, N-(C₁₋₆ alkyl), Y^(K) denotes

Z^(K) denotes

U^(K) denotes

and L stands for

 in which R^(L1) denotes H, OH, O—(C₁₋₆ alkyl), or CO₂—(C₁₋₆ alkyl), andthe tautomers thereof, stereoisomers thereof, salts thereof withpharmacologically acceptable acids or bases, and the prodrugs thereof.3. A compound of the general formula (I) A—B—D—E—G—K—L  (I), in which Astands for H or H—(R^(A1))i^(A) in which R^(A1) denotes

 in which R^(A4) denotes H, or COOH, _(i)A is 1 to 6, _(j)A is 0 or 1,_(k)A is 2 or 3, _(n)A is 1 or 2, the groups R^(A1) being the same ordifferent when _(i)A is greater than 1; B denotes

R^(B3) denotes H, CH₃, or COOH, R^(B4) denotes H, CH₃, COOH, or CHO, inwhich latter case intramolecular acetal formation may take place, _(k)Bis 0 or 1, _(l)B is 1, 2, or 3, _(m)B is 0, 1, 2, or 3, _(n)B is 1, 2,or 3, D stands for a bond E stands for

 in which _(m)E is 0 or 1, R^(E2) denotes H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl, phenyl, diphenylmethyl, or dicyclohexylmethyl, whichgroups may carry up to three identical or different substituentsselected from the group consisting of C₁₋₄ alkyl, OH, O—CH₃, F, and Cl;G stands for

 where _(l)G is 2, 3, or 4 and one of the CH₂ groups in the ring isreplaceable by O, S, NH, or N(C₁₋₃ alkyl),

 in which _(n)G is 0 or 1; K stands for NH—CH₂—Q^(K)  in which Q^(K)denotes

 in which R^(K1) denotes H, CH₃, OH, O—CH₃, F, or Cl, X^(K) denotes O,S, NH, N—CH₃, Y^(K) denotes

Z^(K) denotes

L stands for

 in which R^(L1) denotes H, OH, or CO₂—(C₁₋₆ alkyl), and the tautomersthereof, stereoisomers thereof, salts thereof with pharmacologicallyacceptable acids or bases, and the prodrugs thereof.
 4. A compound ofthe general formula (I) A—B—D—E—G—K—L  (I), in which A stands for H orH—(R^(A1))i^(A) in which R^(A1) denotes

 in which R^(A4) denotes H, or COOH, _(i)A is 1 to 6, _(j)A is 0 or 1,_(k)A is 2 or 3, _(n)A is 1 or 2, the groups R^(A1) being the same ordifferent when _(i)A is greater than 1; B denotes

A—B stands for

 in which R^(B3) denotes H, CH₃, or COOH, R^(B4) denotes H, CH₃, COOH,or CHO, in which latter case intramolecular acetal formation may takeplace, _(k)B is 0 or 1, _(l)B is 1, 2, or 3, _(m)B is 0, 1, 2, or 3,_(n)B is 1, 2, or 3, R^(B6) denotes C,4 alkyl, phenyl, or benzyl, andR^(B7) denotes H, C₁₋₄ alkyl, phenyl, or benzyl, D stands for

 in which R^(D1) denotes H or C₁₋₄ alkyl, R^(D2) denotes a bond or C₁₋₄alkyl, R^(D3) denotes

 in which R^(D4) denotes a bond, C₁₋₄ alkyl, CO, SO₂, or —CH₂—CO, andR^(D6) denotes H or CH₃, E stands for

 in which _(m)E is 0 or 1, R^(E2) denotes H, C₁₋₆ alkyl, or C₃₋₈cycloalkyl, which groups may carry up to three identical or differentsubstituents selected from the group consisting of C₁₋₄ alkyl, OH,O—CH₃, F, and Cl; G stands for

 where _(l)G is 2, 3, or 4 and one of the CH₂ groups in the ring isreplaceable by O, S, NH, or —N(C₁₋₃ alkyl), or

 in which _(n)G is 0 or 1; K stands for NH—CH₂—Q^(K)  in which Q^(K)denotes

 in which R^(K1) denotes H, CH₃, OH, O—CH₃, F, or Cl, X^(K) denotes O,S, NH, N—CH₃, Y^(K) denotes or

Z^(K) denotes

L stands for

 in which R^(L1) denotes H, OH, or CO₂—(C₁₋₆ alkyl), and the tautomersthereof, stereoisomers thereof, salts thereof with pharmacologicallyacceptable acids or bases, and the prodrugs thereof.
 5. A compound ofthe general formula (I) A—B—D—E—G—K—L  (I), in which A stands for H orH—(R^(A1))i^(A) in which R^(A1) denotes

 in which _(i)A is 1 to 6, _(j)A is 0 or 1, _(n)A is 1 or 2, the groupsR^(A1) being the same or different when _(i)A is greater than 1; Bdenotes

 in which _(l)B is 1, 2, or 3, _(m)B is 1 or 2, D stands for a bond, Estands for

 in which _(m)E is 0 or 1, R^(E2) denotes H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, phenyl, diphenylmethyl, or dicyclohexylmethyl, the buildingblock E preferably exhibiting D configuration, G stands for

building block G preferably exhibiting L configuration, K stands forNH—CH₂—Q^(K)  in which Q^(K) denotes

L stands for

 in which R^(L1) denotes H, OH, or CO₂—(C₁₋₆ alkyl), and the tautomersthereof, stereoisomers thereof, salts thereof with pharmacologicallyacceptable acids or bases, and the prodrugs thereof.
 6. A compound ofthe general formula (I) A—B—D—E—G—K—L  (I), in which A stands for H orH—(R^(A1))i^(A) in which R^(A1) denotes

 in which R^(A4) denotes H, or COOH, _(i)A is 1 to 6, _(j)A is 0 or 1,_(k)A is 2 or 3, _(n)A is 1 or 2, the groups R^(A1) being the same ordifferent when _(i)A is greater than 1; B denotes

A—B stands for

 in which R^(B3) denotes H, CH₃, or COOH, R^(B4) denotes H, CH₃, COOH,or CHO, in which latter case intramolecular acetal formation may takeplace, _(k)B is 0 or 1, _(l)B is 1, 2, or 3, _(m)B is 0,1, 2, or 3,_(n)B is 1, 2, or 3, R^(B6) denotes C₁₋₄ alkyl, phenyl, or benzyl, andR^(B7) denotes H, C₁₋₄ alkyl, phenyl, or benzyl, D stands for

 in which R^(D1) denotes H, R^(D2) denotes a bond or C₁₋₄ alkyl, R^(D3)denotes

R^(D4) denotes a bond, C₁₋₄ alkyl, CO, SO₂, or —CH₂—CO, and E stands for

 in which _(m)E is 0 or 1, R^(E2) denotes H, C₁₋₆ alkyl, or C₃₋₈cycloalkyl, which groups may carry up to three identical or differentsubstituents selected from the group consisting of F and Cl; G standsfor

 where _(l)G is 2

or  in which _(n)G is 0, K stands for NH—CH₂—Q^(K)  in which Q^(K)denotes

 in which X^(K) denotes S, Y^(K) denotes ═CH—, or ═N—, Z^(K) denotes═CH—, or ═N—, L stands for

 in which R^(L1) denotes H, or OH, and the tautomers thereof,stereoisomers thereof, salts thereof with pharmacologically acceptableacids or bases, and the prodrugs thereof.
 7. A medicinal drug comprisingat least one compound according to any one of claims 1 to
 6. 8. A methodof using one or more compounds according to any one of claims 1 to 6 forthe preparation of medical drugs for the treatment or prophylaxis ofdeseases which can be alleviated by inhibition of one or more serinproteases.
 9. A method as defined in claim 8, wherein the serin proteasefor a compound according to any one of claims 1 to 3 and 5 is thrombin.10. A method as defined in claim 8, wherein the serin protease for acompound according to any one of claims 1 to 3 and 6 is C1s or C1r.